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Baralle M, Romano M. Age-Related Alternative Splicing: Driver or Passenger in the Aging Process? Cells 2023; 12:2819. [PMID: 38132139 PMCID: PMC10742131 DOI: 10.3390/cells12242819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2023] [Revised: 12/01/2023] [Accepted: 12/08/2023] [Indexed: 12/23/2023] Open
Abstract
Alternative splicing changes are closely linked to aging, though it remains unclear if they are drivers or effects. As organisms age, splicing patterns change, varying gene isoform levels and functions. These changes may contribute to aging alterations rather than just reflect declining RNA quality control. Three main splicing types-intron retention, cassette exons, and cryptic exons-play key roles in age-related complexity. These events modify protein domains and increase nonsense-mediated decay, shifting protein isoform levels and functions. This may potentially drive aging or serve as a biomarker. Fluctuations in splicing factor expression also occur with aging. Somatic mutations in splicing genes can also promote aging and age-related disease. The interplay between splicing and aging has major implications for aging biology, though differentiating correlation and causation remains challenging. Declaring a splicing factor or event as a driver requires comprehensive evaluation of the associated molecular and physiological changes. A greater understanding of how RNA splicing machinery and downstream targets are impacted by aging is essential to conclusively establish the role of splicing in driving aging, representing a promising area with key implications for understanding aging, developing novel therapeutical options, and ultimately leading to an increase in the healthy human lifespan.
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Affiliation(s)
- Marco Baralle
- International Centre for Genetic Engineering and Biotechnology, Padriciano 99, 34149 Trieste, Italy;
| | - Maurizio Romano
- Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 Trieste, Italy
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2
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Taheri M, Hussen BM, Najafi S, Abak A, Ghafouri-Fard S, Samsami M, Baniahmad A. Molecular mechanisms of inhibitor of growth (ING) family members in health and malignancy. Cancer Cell Int 2022; 22:272. [PMID: 36056353 PMCID: PMC9438315 DOI: 10.1186/s12935-022-02693-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Accepted: 08/22/2022] [Indexed: 11/10/2022] Open
Abstract
ING genes belong to family of tumor suppressor genes with regulatory functions on cell proliferation, apoptosis, and cellular senescence. These include a family of proteins with 5 members (ING1-5), which are downregulated in human malignancies and/or affected by pathogenic mutations. ING proteins are highly evolutionarily conserved proteins containing several domains through which bind to chromatin structures by exerting their effects as readers of histone modification marks, and also binding to proteins like p53 involved in biological processes such as cell cycle regulation. Further, they are known as subunits of histone acetylation as well as deacetylation complexes and so exert their regulatory roles through epigenetic mechanisms. Playing role in restriction of proliferative but also invasive potentials of normal cells, INGs are particularly involved in cancer development and progression. However, additional studies and experimental confirmation are required for these models. This paper highlights the potential impact that INGs may have on the development of human cancer and explores what new information has recently arise on the functions of ING genes.
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Affiliation(s)
- Mohammad Taheri
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.,Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Bashdar Mahmud Hussen
- Department of Pharmacognosy, College of Pharmacy, Hawler Medical University, Kurdistan Region, Erbil, Iraq.,Center of Research and Strategic Studies, Lebanese French University, Erbil, Kurdistan Region, Iraq
| | - Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atefe Abak
- Skull Base Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Majid Samsami
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Aria Baniahmad
- Institute of Human Genetics, Jena University Hospital, Jena, Germany.
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Inhibitor of Growth Factors Regulate Cellular Senescence. Cancers (Basel) 2022; 14:cancers14133107. [PMID: 35804879 PMCID: PMC9264871 DOI: 10.3390/cancers14133107] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Revised: 06/20/2022] [Accepted: 06/21/2022] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Five members of the Inhibitor of Growth (ING) family share a highly conserved plant homeodomian with affinity to the specific histone modification H3K4me3. Since some ING family members are preferentially associated with histone acetyltransferaseactivity while other members with histone deacetlyse activity, the ING family membres are epigenetic regulators. Interestingly, ING members can regulate the induction cellular senescence in both primray untransformed human cells as well as human cancer cells. We discuss here the up-to-date knowledge about their regulatory activity within the cellular senescent program. Abstract The Inhibitor of Growth (ING) proteins are a group of tumor suppressors with five conserved genes. A common motif of ING factors is the conserved plant homeodomain (PHD), with which they bind to chromatin as readers of the histone mark trimethylated histone H3 (H3K4me3). These genes often produce several protein products through alternative splicing events. Interestingly, ING1 and ING2 participate in the establishment of the repressive mSIN3a-HDAC complexes, whereas ING3, ING4, and ING5 are associated with the activating HAT protein complexes. In addition to the modulation of chromatin’s structure, they regulate cell cycle transition, cellular senescence, repair of DNA damage, apoptosis, and angiogenic pathways. They also have fundamental effects on regulating cellular senescence in cancer cells. In the current review, we explain their role in cellular senescence based on the evidence obtained from cell line and animal studies, particularly in the context of cancer.
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Zhao S, Zheng HC. mRNA and protein of p33ING1 in normal and cancer tissues. Transl Cancer Res 2020; 9:3623-3633. [PMID: 35117725 PMCID: PMC8798731 DOI: 10.21037/tcr.2020.04.28] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2019] [Accepted: 04/01/2020] [Indexed: 01/22/2023]
Abstract
Background Inhibitor growth protein 1 (ING1) is a tumor suppressor, and its down-regulation is involved in the progression and aggressive phenotypes of human malignancies through its interactions with the H3K4me3 and p53. Methods We collected datasets to analyze the relationship between ING1b mRNA expression and accumulative survival rate, and carried out immunohistochemistry analyses to determine the expression profiles of the p33ING1 protein on the mouse, normal human, and human cancer tissue microarrays. Results Compared with normal tissues, the ING1b mRNA was highly expressed in various types of cancer tissues, including, colorectal, lung, and breast cancers, and was positively correlated with the overall survival rate of gastric cancer patients. In mouse tissues, the subcellular location of p33ING1 was frequently nuclear; however, it was occasionally cytoplasmic or nucleocytoplasmic. There was a positive detection in the neuron body, a part of glial cells, the glandular epithelium of the stomach, intestines, breast, hepatocytes, heart, skeletal muscle cells, the bronchial and alveolar epithelium, and nephric tubules. In human tissues, the p33ING1 protein, apart from its cytoplasmic distribution, was distributed in the nuclei of the tongue, esophagus, stomach, intestine, lung, trachea, skin, appendix, cervix, endometrium, ovary, and breast. p33ING1 immunoreactivity was strongly detected in the stomach, trachea, skin, cervix, and breast, while it was weak in the other tissues. The positive rate of p33ING1 was 41.0% in the tested cancer entities (489/1,194). In general, p33ING1 expression was restricted to only the cytoplasm for all cancers, whereas it was found in the nucleus of renal clear cells, ovarian and colorectal cancers. Among them, p33ING1 was expressed in more than half of squamous cell carcinomas derived from the esophagus and cervix, while it was rarely expressed in hepatocellular (21.0%) and renal clear cell carcinoma (19.4%). Conclusions The findings suggest that p33ING1 might be participated in the repair and regeneration of organs or tissues the repair and regeneration of organs or tissue, and the carcinogenesis of the highly proliferative epithelium.
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Affiliation(s)
- Shuang Zhao
- Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
| | - Hua-Chuan Zheng
- Department of Experimental Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China
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Fallahnezhad S, Nikbakht M, Shokri S. Expression of P33(ING1b) Protein in Colorectal Cancer. Middle East J Dig Dis 2016; 8:44-50. [PMID: 26933481 PMCID: PMC4773082 DOI: 10.15171/mejdd.2016.06] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND
Colorectal cancer (CRC) is the second most common malignancy in the world. However, its mortality rate can be reduced if diagnosed early. P33ING1b is a tumor suppressor protein, which plays a role in growth control and apoptosis. Suppression of p33ING1b is associated with the loss of cellular growth control. However, p33 ING1b expression in CRC and its correlations with clinicopathological factors have been less studied. The aim of this study was to examine p33ING1b expression in patients with CRC and evaluate its potential correlations with clinicopathological factors.
METHODS
P33ING1b protein expression was examined in 70 cases of CRC tissue samples and their corresponding neighboring normal tissues by immunhistochemistry. Moreover, p33ING1b expression in CRC and its correlations with clinicopathological variables including patients’ sex and age, tumor type, location, stage, and differentiation grade were examined.
RESULTS
P33ING1b expression was significantly lower in tumor samples compared with the normal adjacent samples (p<0.002).
CONCLUSION
Low expression of P33ING1b in patients with colorectal cancer, may be an important molecular event in the pathogenesis of colorectal cancer. Our data suggest that reduced expression of p33ING1b may be contribute to tumor genesis and accompanied by the loss of cellular growth control. In fact cell growth is out of control in lower expression of P33 and dysfunctional program cell death. P33 expression might explain the etiology of CRC for reducing the expression of tumor suppressor proteins.
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Affiliation(s)
- Somayeh Fallahnezhad
- Department of Anatomical Sciences and Cell Biology, Medical Faculty, Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran
| | - Mehdi Nikbakht
- Department of Anatomical Sciences and Cell Biology, Medical Faculty, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Saeed Shokri
- Department of Anatomical Sciences, Medical Faculty, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran
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Jia AI, Lv Y, Guo X, Ren LI, Qin J. Ectopic expression of p33 ING1b suppresses proliferation and induces apoptosis in colonic adenocarcinoma cells. Oncol Lett 2015; 10:1517-1522. [PMID: 26622701 DOI: 10.3892/ol.2015.3385] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 05/12/2015] [Indexed: 12/12/2022] Open
Abstract
Inhibitor of growth 1b (ING1b) is considered to be a class II tumor suppressor gene. Although decreased expression of p33ING1b has previously been reported in colorectal cancer (CRC), its role in CRC has remained to be elucidated. The present study was designed to assess the function of p33ING1b in CRC and to further evaluate its underlying mechanisms of action. Western blot analysis confirmed that ING1b gene expression was significantly decreased in CRC tissues compared with that of adjacent non-tumorous colorectal tissues. Furthermore, recombinant adenovirus-mediated ectopic expression of p33ING1b resulted in growth inhibition, G1-phase cell cycle arrest and apoptosis in the SW480, HT29 and LoVo colorectal adenocarcinoma cell lines. The results suggested that the downregulation of ING1b contributes to colorectal carcinogenesis and that ectopic expression of ING1b may be a potentially useful therapeutic approach for CRC.
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Affiliation(s)
- A I Jia
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Yifei Lv
- Department of Gastroenterology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - Xueyan Guo
- Department of Gastroenterology, Shaanxi Provincial People's Hospital, Xi'an, Shaanxi 710068, P.R. China
| | - L I Ren
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
| | - Jie Qin
- Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
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Igci M, Arslan A, Erturhan S, Igci YZ, Pala E, Gogebakan B, Karakok M, Cakmak EA, Cengiz B. Loss of heterozygosity of chromosome 13q33-34 region and molecular analysis of ING1 and p53 genes in bladder carcinoma. Mol Biol Rep 2014; 42:507-16. [DOI: 10.1007/s11033-014-3794-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2013] [Accepted: 10/10/2014] [Indexed: 01/17/2023]
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The expression of p33(ING1), p53, and autophagy-related gene Beclin1 in patients with non-small cell lung cancer. Tumour Biol 2011; 32:1113-21. [PMID: 21779982 DOI: 10.1007/s13277-011-0211-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2011] [Accepted: 07/05/2011] [Indexed: 12/19/2022] Open
Abstract
The purpose of this study was to investigate the expressions of tumor inhibitor of growth (ING1) gene p33ING1, p53, and autophagy-related gene Beclin1 in human non-small cell lung cancer (NSCLC), and the correlation between their expressions with clinical pathological features and clinical significance. The research can provide new ideas and experimental evidence for early diagnosis and biotherapy for NSCLC in the future. The human NSCLC tissues and surrounding non-cancerous tissues were collected from surgical operation. The expressions of mRNA or protein of p33ING1, p53, and Beclin1 were detected by using of reverse transcription polymerase chain reaction or Western blot in these tissues. The results were used to analyze the relationships between these gene expressions with the developing of NSCLC and clinical pathological features. The expressions of mRNA or protein of p33ING1 and Beclin1 in NSCLC tissues were significantly lower than that in surrounding noncancerous tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in well- and middle-differentiated NSCLC tissues were lower than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in presence of lymph nodes metastasis were lower than those in absence of lymph nodes metastasis (p < 0.05). The expressions of mRNA or protein of p33ING1 and Beclin1 in patients of pathological stage (stages I-II) were higher than those in pathological stage (stages III-IV) (p < 0.05). But the expression of protein of mutant-type p53 in NSCLC tissues was significantly higher than that in surrounding non-cancerous tissues (p < 0.05). The expressions of protein of mutant-type p53 in well- and middle-differentiated NSCLC tissues were higher than those in poor-differentiated NSCLC tissues (p < 0.05). The expressions of protein of mutant-type p53 in presence of lymph nodes metastasis were higher than those in absence of lymph nodes metastasis (p < 0.05). The expressions of protein of mutant-type p53 in patients of pathological stage (stages I-II) were lower than those in pathological stage (stages III-IV) (p < 0.05). These expression changes of p33ING1, p53, and autophagy-related Beclin1 genes were associated with tumor cell differentiation, lymph nodes metastasis, and pathological stage of NSCLC. But these expression changes of these three genes were not associated with gender, age, size of primary carcinoma, histological type of NSCLC (p > 0.05). The expression of mRNA of p53 and Beclin1 were correlated with p33ING1 mRNA expression in NSCLC tissues (p < 0.05). The activity changes of tumor inhibitor of growth, autophagy, and apoptosis may be related to the emergence and the development of NSCLC. The combined detection of p33ING1, p53, and Beclin1 genes and proteins will be helpful for early diagnosis and prognosis judgment for NSCLC, and can provide experimental evidence for biotherapy of NSCLC.
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Aguissa-Touré AH, Wong RPC, Li G. The ING family tumor suppressors: from structure to function. Cell Mol Life Sci 2011; 68:45-54. [PMID: 20803232 PMCID: PMC11114739 DOI: 10.1007/s00018-010-0509-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2010] [Revised: 07/31/2010] [Accepted: 08/10/2010] [Indexed: 12/24/2022]
Abstract
The Inhibitor of Growth (ING) proteins belong to a well-conserved family which presents in diverse organisms with several structural and functional domains for each protein. The ING family members are found in association with many cellular processes. Thus, the ING family proteins are involved in regulation of gene transcription, DNA repair, tumorigenesis, apoptosis, cellular senescence and cell cycle arrest. The ING proteins have multiple domains that are potentially capable of binding to many partners. It is conceivable, therefore, that such proteins could function similarly within protein complexes. In this case, within this family, each function could be attributed to a specific domain. However, the role of ING domains is not definitively clear. In this review, we summarize recent advances in structure-function relationships in ING proteins. For each domain, we describe the known biological functions and the approaches utilized to identify the functions associated with ING proteins.
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Affiliation(s)
- Almass-Houd Aguissa-Touré
- Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6 Canada
| | - Ronald P. C. Wong
- Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6 Canada
| | - Gang Li
- Department of Dermatology and Skin Science, Jack Bell Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 2660 Oak Street, Vancouver, BC V6H 3Z6 Canada
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Steilmann C, Cavalcanti MCO, Bergmann M, Kliesch S, Weidner W, Steger K. Aberrant mRNA expression of chromatin remodelling factors in round spermatid maturation arrest compared with normal human spermatogenesis. Mol Hum Reprod 2010; 16:726-33. [DOI: 10.1093/molehr/gaq054] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
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COLES ANDREWH, JONES STEPHENN. The ING gene family in the regulation of cell growth and tumorigenesis. J Cell Physiol 2009; 218:45-57. [PMID: 18780289 PMCID: PMC2872195 DOI: 10.1002/jcp.21583] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
The five members of the inhibitor of growth (ING) gene family have garnered significant interest due to their putative roles as tumor suppressors. However, the precise role(s) of these ING proteins in regulating cell growth and tumorigenesis remains uncertain. Biochemical and molecular biological analysis has revealed that all ING members encode a PHD finger motif proposed to bind methylated histones and phosphoinosital, and all ING proteins have been found as components of large chromatin remodeling complexes that also include histone acetyl transferase (HAT) and histone deacetylase (HDAC) enzymes, suggesting a role for ING proteins in regulating gene transcription. Additionally, the results of forced overexpression studies performed in tissue culture have indicated that several of the ING proteins can interact with the p53 tumor suppressor protein and/or the nuclear factor-kappa B (NF-kappaB) protein complex. As these ING-associated proteins play well-established roles in numerous cell processes, including DNA repair, cell growth and survival, inflammation, and tumor suppression, several models have been proposed that ING proteins act as key regulators of cell growth not only through their ability to modify gene transcription but also through their ability to alter p53 and NF-kappaB activity. However, these models have yet to be substantiated by in vivo experimentation. This review summarizes what is currently known about the biological functions of the five ING genes based upon in vitro experiments and recent mouse modeling efforts, and will highlight the potential impact of INGs on the development of cancer.
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Affiliation(s)
- ANDREW H. COLES
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts
| | - STEPHEN N. JONES
- Department of Cell Biology, University of Massachusetts Medical School, Worcester, Massachusetts
- Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts
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12
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NAD(P)H quinone oxidoreductase 1 inhibits the proteasomal degradation of the tumour suppressor p33(ING1b). EMBO Rep 2008; 9:576-81. [PMID: 18388957 DOI: 10.1038/embor.2008.48] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2008] [Accepted: 03/03/2008] [Indexed: 12/27/2022] Open
Abstract
The tumour suppressor p33(ING1b) ((ING1b) for inhibitor of growth family, member 1b) is important in cellular stress responses, including cell-cycle arrest, apoptosis, chromatin remodelling and DNA repair; however, its degradation pathway is still unknown. Recently, we showed that genotoxic stress induces p33(ING1b) phosphorylation at Ser 126, and abolishment of Ser 126 phosphorylation markedly shortened its half-life. Therefore, we suggest that Ser 126 phosphorylation modulates the interaction of p33(ING1b) with its degradation machinery, stabilizing this protein. Combining the use of inhibitors of the main degradation pathways in the nucleus (proteasome and calpains), partial isolation of the proteasome complex, and in vitro interaction and degradation assays, we set out to determine the degradation mechanism of p33(ING1b). We found that p33(ING1b) is degraded in the 20S proteasome and that NAD(P)H quinone oxidoreductase 1 (NQO1), an oxidoreductase previously shown to modulate the degradation of p53 in the 20S proteasome, inhibits the degradation of p33(ING1b). Furthermore, ultraviolet irradiation induces p33(ING1b) phosphorylation at Ser 126, which, in turn, facilitates its interaction with NQO1.
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13
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Rottmann S, Lüscher B. The Mad side of the Max network: antagonizing the function of Myc and more. Curr Top Microbiol Immunol 2006; 302:63-122. [PMID: 16620026 DOI: 10.1007/3-540-32952-8_4] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
A significant body of evidence has been accumulated that demonstrates decisive roles of members of the Myc/Max/Mad network in the control of various aspects of cell behavior, including proliferation, differentiation, and apoptosis. The components of this network serve as transcriptional regulators. Mad family members, including Mad1, Mxi1, Mad3, Mad4, Mnt, and Mga, function in part as antagonists of Myc oncoproteins. At the molecular level this antagonism is reflected by the different cofactor/chromatin remodeling complexes that are recruited by Myc and Mad family members. One important function of the latter is their ability to repress gene transcription. In this review we summarize the current view of how this repression is achieved and what the consequences of Mad action are for cell behavior. In addition, we point out some of the many aspects that have not been clarified and thus leave us with a rather incomplete picture of the functions, both molecular and at the cellular level, of Mad family members.
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Affiliation(s)
- S Rottmann
- Abteilung Biochemie und Molekularbiologie, Institut für Biochemie, Klinikum der RWTH, Pauwelsstrasse 30, 52074 Aachen, Germany
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14
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Bassal S, El-Osta A. DNA damage detection and repair, and the involvement of epigenetic states. Hum Mutat 2006; 25:101-9. [PMID: 15643607 DOI: 10.1002/humu.20130] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Chromatin is a highly dynamic structure that acts alternately as a substrate and a template in a number of critical biological processes. Modification of chromatin is pertinent and is responsible for a number of nuclear processes, including DNA repair, replication, transcription, and recombination. The purpose of this review is to discuss specific interactions between chromatin remodeling, DNA repair, and transcription. These areas are demonstrated to share commonality, particularly with a number of key molecules that appear to have roles in a number of pathways. The implications of pathway cross-over and communication form a seamless continuation of genomic integrity and stability.
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Affiliation(s)
- Sahar Bassal
- Alfred Medical Research and Education Precinct, Baker Medical Research Institute, Epigenetics in Human Health and Disease Laboratory, Prahran, Australia
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15
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Wagner MJ, Helbing CC. Multiple variants of the ING1 and ING2 tumor suppressors are differentially expressed and thyroid hormone-responsive in Xenopus laevis. Gen Comp Endocrinol 2005; 144:38-50. [PMID: 15955533 DOI: 10.1016/j.ygcen.2005.04.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2004] [Revised: 04/19/2005] [Accepted: 04/19/2005] [Indexed: 10/25/2022]
Abstract
The tumor suppressor candidate, inhibitor of growth (ING) is implicated in the control of apoptosis, cell cycle progression, chemosensitivity, and senescence. There are at least five different genes in mammals, ING1-ING5, and there is limited evidence that multiple transcript variants exist for ING1 that encode proteins with different functions. No variants have yet been reported for other ING genes. Here, we report the isolation of seven Xenopus laevis (x)ING1 and three xING2 transcript variants and give the first evidence for their independent regulation by thyroid hormone (TH). Comparison with mammalian genes reveals conservation in gene structure. xING1 and xING2 transcript variants are differentially expressed in adult tissues with the greatest number of variants expressed at high levels in brain, testis, and eye. During metamorphosis of the tadpole into a frog, the hindlimb, tail, and brain undergo growth, apoptosis, or remodeling, respectively. We show that xING1 and xING2 transcript variants are significantly reduced in the hindlimb while many variants increase in the tail. These transcript variants remain largely unchanged in the brain during this developmental period. By exposing premetamorphic tadpoles to TH, a precocious metamorphosis is induced. We identify specific variants whose steady state levels are significantly affected by TH at 24 and 48h of exposure. Although several of the variants show expression patterns reminiscent of that observed in natural metamorphosis, the results indicate that additional factors may be involved to influence the steady state transcript levels during development.
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Affiliation(s)
- Mary J Wagner
- Department of Biochemistry and Microbiology, University of Victoria, P.O. Box 3055, Victoria, BC, Canada V8W 3P6
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Gong W, Suzuki K, Russell M, Riabowol K. Function of the ING family of PHD proteins in cancer. Int J Biochem Cell Biol 2005; 37:1054-65. [PMID: 15743678 DOI: 10.1016/j.biocel.2004.09.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2004] [Revised: 08/19/2004] [Accepted: 09/08/2004] [Indexed: 02/08/2023]
Abstract
The ING genes encode a family of at least seven proteins with conserved plant homeodomain (PHD)-type zinc fingers in their C-termini. The founding member, ING1, is capable of binding to and affecting the activity of histone acetyltransferase (HAT), histone deacetylase (HDAC), and factor acetyltransferase (FAT) protein complexes. Some ING proteins are involved in transcriptional regulation of genes, such as the p53-inducible genes p21 and Bax. Others have been found to affect post-translational modifications, exemplified by the ING2-induced acetylation of p53 on the same site deacetylated by the Sir2 HDAC. Upon UV irradiation, ING1 causes cell cycle arrest and interacts with proliferating cell nuclear antigen to promote DNA repair or induce apoptosis in cells to prevent tumorigenesis depending upon the severity of DNA damage. It is very likely that, by linking DNA repair, apoptosis and chromatin remodeling to the transcriptional regulation of critical genes, ING1 exerts it tumor suppressor functions by helping maintain genomic stability. Therefore, ING proteins, which are down-regulated in a broad variety of cancer types, are able to restrict cell growth and proliferation, induce apoptosis, and modulate cell cycle progression, which strongly supports the notion that ING family proteins act as class II tumor suppressors.
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Affiliation(s)
- Wei Gong
- Department of Biochemistry, Faculty of Medicine, University of Calgary HSC, 370 Heritage Medical Research Building, 3330 Hospital Drive, NW, Calgary, Alta., Canada T2N 4N1
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Shen DH, Chan KYK, Khoo US, Ngan HYS, Xue WC, Chiu PM, Ip P, Cheung ANY. Epigenetic and genetic alterations of p33 ING1b in ovarian cancer. Carcinogenesis 2005; 26:855-63. [PMID: 15677627 DOI: 10.1093/carcin/bgi011] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
p33ING1b is a candidate tumor suppressor gene and a nuclear protein. We investigated whether genetic and epigenetic mechanisms affect p33ING1b expression in ovarian cancer thus contributing toward its pathogenesis. A total of 111 ovarian cancers collected from Beijing and Hong Kong were used for this study. Weak or negative p33ING1b protein expression was demonstrated by immunohistochemistry on tissue microarray in 28/111 cases. Real-time quantitative RT-PCR also showed overall significant reduction of p33ING1b mRNA expression (P = 0.0137), with 53.1% (17/32) cases showing 2- to 5-fold reduction and absence of expression. The reduction of mRNA expression in cancer correlated with decreased p33ING1b protein expression (P < 0.0001). While no p33ING1b mutation was found, allelic loss at the p33ING1b locus was demonstrated in 25% (8/32) cases. The allelic loss profiles also showed statistical significant correlation with reduction of p33ING1b protein and mRNA expression (P = 0.031 and 0.030). Promoter methylation as assessed by methylation specific PCR was found in 23.9% (21/88) cases analyzed. Bisulfite sequencing results confirmed the p33ING1b promoter methylation status of these methylation positive cases. Statistical significant correlation between methylation and mRNA expression (P = 0.006) was demonstrated. Treatment with demethylating drug, 5'-aza-2'-deoxycytidine, resulted in dosage-dependent elevated mRNA expression of p33ING1b in ovarian cancer cell lines. This is the first study reporting epigenetic mechanism regulating the p33ING1b expression. Our findings support that genetic and epigenetic alteration of p33ING1b are likely to contribute towards the pathogenesis of ovarian cancers.
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MESH Headings
- Adenocarcinoma, Clear Cell/genetics
- Adenocarcinoma, Clear Cell/metabolism
- Adenocarcinoma, Clear Cell/pathology
- Antimetabolites, Antineoplastic/pharmacology
- Azacitidine/analogs & derivatives
- Azacitidine/pharmacology
- Carcinoma, Endometrioid/genetics
- Carcinoma, Endometrioid/metabolism
- Carcinoma, Endometrioid/pathology
- Case-Control Studies
- Cell Cycle Proteins
- CpG Islands
- Cystadenocarcinoma, Mucinous/genetics
- Cystadenocarcinoma, Mucinous/metabolism
- Cystadenocarcinoma, Mucinous/pathology
- Cystadenocarcinoma, Serous/genetics
- Cystadenocarcinoma, Serous/metabolism
- Cystadenocarcinoma, Serous/pathology
- DNA Methylation
- DNA-Binding Proteins
- Decitabine
- Female
- Gene Expression Regulation, Neoplastic
- Genes, Tumor Suppressor
- Humans
- Immunoenzyme Techniques
- Inhibitor of Growth Protein 1
- Intracellular Signaling Peptides and Proteins
- Loss of Heterozygosity
- Mutation/genetics
- Nuclear Proteins
- Ovarian Neoplasms/genetics
- Ovarian Neoplasms/metabolism
- Ovarian Neoplasms/pathology
- Ovary/metabolism
- Ovary/pathology
- Promoter Regions, Genetic/genetics
- Proteins/genetics
- RNA, Messenger/genetics
- RNA, Messenger/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Cells, Cultured
- Tumor Suppressor Proteins
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Affiliation(s)
- Dan-Hua Shen
- Department of Pathology, People's Hospital, Peking University, Beijing, Republic of China
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18
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Goeman F, Thormeyer D, Abad M, Serrano M, Schmidt O, Palmero I, Baniahmad A. Growth inhibition by the tumor suppressor p33ING1 in immortalized and primary cells: involvement of two silencing domains and effect of Ras. Mol Cell Biol 2005; 25:422-31. [PMID: 15601862 PMCID: PMC538761 DOI: 10.1128/mcb.25.1.422-431.2005] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023] Open
Abstract
ING1 was identified as an inhibitor of growth and has been described as a tumor suppressor. Furthermore, the expression of ING1 is induced in senescent cells and antisense ING1 extends the proliferative life span of primary human fibroblasts. Cooperation of p33ING1 with p53 has been suggested to be an important function of ING1 in cell cycle control. Intriguingly, it has been shown that p33ING1 is associated with histone acetylation as well as with histone deacetylation function. Here we show that p33ING1 is a potent transcriptional silencer in various cell types. However, the silencing function is independent of the presence of p53. By use of deletion mutants two potent autonomous and transferable silencing domains were identified, but no evidence of an activation domain was found. The amino (N)-terminal silencing domain is sensitive to the histone deacetylase inhibitor trichostatin A (TSA) whereas the carboxy-terminal silencing function is resistant to TSA, suggesting that p33ING1 confers gene silencing through both HDAC-dependent and -independent mechanisms. Interestingly, the presence of oncogenic Ras, which is able to induce premature senescence, increases the p33ING1-mediated silencing function. Moreover, ING1-mediated silencing was reduced by coexpressing dominant-negative Ras or by treatment with the mitogen-activated protein kinase inhibitor PD98059 but not by treatment with SB203580, an inhibitor of the p38 pathway. In addition, we show that both silencing domains of ING1 are involved in cell cycle control, as measured by inhibition of colony formation of immortalized cells and by thymidine incorporation of primary human diploid fibroblasts (HDF). Interestingly, p33ING1 expression induces features of cellular senescence in HDFs.
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Affiliation(s)
- Frauke Goeman
- Genetic Institute, Justus-Liebig-University, Heinrich-Buff-Ring 58-62, 35392 Giessen, Germany
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19
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Yu GZ, Zhu MH, Zhu Z, Ni CR, Zheng JM, Li FM. Genetic alterations and reduced expression of tumor suppressor p33 ING1b in human exocrine pancreatic carcinoma. World J Gastroenterol 2004; 10:3597-601. [PMID: 15534913 PMCID: PMC4611999 DOI: 10.3748/wjg.v10.i24.3597] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To detect the expression of p33ING1b protein and the change of p33ING1b gene in pancreatic carcinoma and to evaluate the significance of p33ING1b in pancreatic cell carcinogenesis.
METHODS: Pathological specimens from pancreatic carcinoma and matched non-tumor pancreatic tissues were examined for p33ING1b expression and mutation by immunohistochemistry, polymerase chain reaction single-strand conformation polymorphisms (PCR-SSCP) and loss of heterozygosity (LOH).
RESULTS: The rate of p33ING1b protein expression was 85% (34/40). A single germline missense mutation was detected in 1 of 40 tumors located at codon 215: TGC-TCC (Cys-Ser). Fourteen (60.9%) of 23 tumor samples showed LOH in all of the informative markers tested, but no mutation was detected in these tumors and only two of the informative tumors lacked expressions of p33ING1b protein.
CONCLUSION: Mutation and loss of expression are not the main reasons for the disfunction of p33ING1b in pancreatic carcinoma, an abnormality at the level of chromosome and/or transcription may inhibit their normal functions, potentially contributing to pancreatic cell carcinogenesis.
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Affiliation(s)
- Guan-Zhen Yu
- Department of Pathology, Changhai Hospital, Second Military Medical University, Shanghai 200433, China
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20
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Nikolaev AY, Papanikolaou NA, Li M, Qin J, Gu W. Identification of a novel BRMS1-homologue protein p40 as a component of the mSin3A/p33(ING1b)/HDAC1 deacetylase complex. Biochem Biophys Res Commun 2004; 323:1216-22. [PMID: 15451426 DOI: 10.1016/j.bbrc.2004.08.227] [Citation(s) in RCA: 59] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2004] [Indexed: 11/26/2022]
Abstract
Repression of gene transcription is mediated by histone deacetylases containing repressor-co-repressor complexes, which are recruited to promoters of target genes via interactions with sequence-specific transcription factors. The mammalian Sin3A co-repressor complex contains a core of at least seven proteins including the pRb-interacting protein RBP1 and a putative tumor suppressor p33(ING1b). By biochemical purification and mass spectrometry, we have identified a novel component p40 from this complex. p40 bears homology to both yeast Sds3, a component of yeast histone deacetylase complexes, and its mammalian homologue mSds3. The p40-associated complex purified from human cells shows a strong histone deacetylase activity. When tethered to a Gal-DNA binding domain, the Gal-p40 is able to significantly repress transcription of a Gal-luciferase promoter. Interestingly, database analysis reveals that p40 is also highly homologous to BRMS1, a breast carcinoma metastasis suppressor, and overexpression of p40 in human cells can significantly inhibit cell growth. Thus, our data indicate that p40 may be critically involved in transcription repression of cell growth-associated gene expression by recruiting the HDAC1 deacetylase complex.
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Affiliation(s)
- Anatoly Y Nikolaev
- Department of Pathology, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
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21
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Abstract
The ING1 gene was originally cloned as a candidate tumor suppressor of human breast cancer, and recent studies suggest that ING1 proteins are involved in chromatin remodeling functions via physical association with both histone acetyltransferases (HATs) and histone deacetylases (HDACs). Both CREB binding protein (CBP) and the related p300 proteins show a marked preference for binding to complexes containing p33ING1b, one of the major ING1 isoforms, whereas HDAC immunocomplexes contain equal amounts of p33ING1b and p47ING1a. This observation is interesting, given that p33ING1b can selectively increase histone H3 and H4 acetylation when micro-injected into individual cells, whereas p47ING1a inhibits histone acetylation. We investigated whether p33ING1b modulated the transcriptional activity of estrogen receptor (ER)alpha. In cells transfected with increasing concentrations of a mammalian expression vector encoding p33ING1b, estrogen-induced ER alpha transcriptional activity was found to increase in a dose-dependent manner. As p33ING1b expression levels increased, transcription of an ER-responsive reporter gene by either estrogen-inducible full-length ER alpha or the activation function (AF) 1 deletion mutant was enhanced, while the AF2 deletion mutant was unaffected by the presence of p33ING1b. These results showed that p33ING1b enhanced estrogen-induced ER alpha activity through the AF2 domain. Our data demonstrate that p33ING1b acts like a coactivator for ER alpha and stimulates estrogen-induced ER alpha transcriptional activity consistent with a function for p33ING1b in chromatin remodeling.
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Affiliation(s)
- Tatsuya Toyama
- Department of Breast Surgery, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
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22
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Campos EI, Xiao H, Li G. Generation of a Polyclonal Antibody Specifically Against the p33ING1bTumor Suppressor. J Immunoassay Immunochem 2004; 25:71-80. [PMID: 15038618 DOI: 10.1081/ias-120027227] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The p33(ING1b) tumor suppressor protein plays a prominent role in cellular stress responses including cell cycle arrest, DNA repair, apoptosis, and chromatin remodeling. As the main product of the inhibitor of growth 1 (ING1) gene, p33(ING1b) is the most intensively studied protein of the ING family. So far, most ING1 antibodies have been raised against full-length proteins. Since all ING1 isoforms share an identical carboxyl-terminus, and commercially available ING1 antibodies often lack specificity, we sought to develop a polyclonal antibody capable of specifically recognizing the p33(ING1b) protein. Here, we describe the development and characterization of the p33(ING1b)-specific antibody.
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Affiliation(s)
- E I Campos
- Department of Medicine, Division of Dermatology, University of British Columbia, Vancouver, British Columbia, Canada
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23
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Lawrence CW. Cellular functions of DNA polymerase zeta and Rev1 protein. ADVANCES IN PROTEIN CHEMISTRY 2004; 69:167-203. [PMID: 15588843 DOI: 10.1016/s0065-3233(04)69006-1] [Citation(s) in RCA: 116] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Affiliation(s)
- Christopher W Lawrence
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
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24
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Toyama T, Iwase H, Yamashita H, Hara Y, Sugiura H, Zhang Z, Fukai I, Miura Y, Riabowol K, Fujii Y. p33(ING1b) stimulates the transcriptional activity of the estrogen receptor alpha via its activation function (AF) 2 domain. J Steroid Biochem Mol Biol 2003; 87:57-63. [PMID: 14630091 DOI: 10.1016/s0960-0760(03)00388-1] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The ING1 gene was originally cloned as a candidate tumor suppressor of human breast cancer, and recent studies suggest that ING1 proteins are involved in chromatin remodeling functions via physical association with both histone acetyltransferases (HATs) and histone deacetylases (HDACs). In this study, we investigated whether p33(ING1b), one of the major ING1 isoforms, modulated the transcriptional activity of estrogen receptor (ER) alpha. In Cos-7 cells transfected with increasing concentrations of a mammalian expression vector encoding for p33(ING1b), estrogen-induced ERalpha transcriptional activity was found to increase in a dose-dependent manner. As p33(ING1b) expression levels increased, transcription of an ER-responsive reporter gene by either estrogen-inducible full-length ERalpha or activation function (AF) 1 deletion mutant was enhanced, while the AF2 deletion mutant was unaffected by the presence of p33(ING1b). These results showed that p33(ING1b) enhanced estrogen-induced ERalpha activity through the AF2 domain. Our data also demonstrated that the antiestrogens inhibited the transcriptional activity of ERalpha as stimulated by p33(ING1b). Furthermore, a weak physical association was observed between in vitro translated p33(ING1b) and ERalpha. Our data presented here demonstrate that p33(ING1b) acts like a coactivator for ERalpha and stimulates estrogen-induced ERalpha transcriptional activity consistent with a function for p33(ING1b) in chromatin remodeling.
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Affiliation(s)
- Tatsuya Toyama
- Department of Surgery II, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan.
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25
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Nouman GS, Anderson JJ, Lunec J, Angus B. The role of the tumour suppressor p33 ING1b in human neoplasia. J Clin Pathol 2003; 56:491-6. [PMID: 12835293 PMCID: PMC1769994 DOI: 10.1136/jcp.56.7.491] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/26/2003] [Indexed: 12/25/2022]
Abstract
The inhibitor of growth (ING) genes (ING1-4) probably descend from tumour suppressor genes. ING1 was the first to be identified and later isolated using an approach to detect genes whose expression is suppressed in cancer. The others were isolated through homology and similarity searches in human and mouse databases. All members contain a plant homeodomain involved in macromolecule recognition. Apart from the extensively studied ING1, little is known about the number of transcripts encoded by the other members or their gene structure. ING1 encodes several differentially spliced mRNAs, which may produce a family of proteins. The most widely expressed protein isoform is p33(INGb1), which is involved in restriction of cell growth and proliferation, apoptosis, tumour anchorage independent growth, cellular senescence, maintenance of genomic stability, and modulation of cell cycle checkpoints. ING1 gene mutation is uncommon in cancer, although the subcellular localisation of p33(INGb1) may have an effect on its function. The p33(INGb1) cellular compartmental shift from the nucleus to the cytoplasm may cause loss of normal cellular function, and may play a central role in the pathogenesis of several cancers.
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Affiliation(s)
- G S Nouman
- Pathology Department, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4PH, UK.
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26
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Ko JK, Lee MJ, Cho SH, Cho JA, Lee BY, Koh JS, Lee SS, Shim YH, Kim CW. Bfl-1S, a novel alternative splice variant of Bfl-1, localizes in the nucleus via its C-terminus and prevents cell death. Oncogene 2003; 22:2457-65. [PMID: 12717423 DOI: 10.1038/sj.onc.1206274] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Bfl-1 is an antiapoptotic Bcl-2 family member and a mouse A1 homologue. The mouse A1 has been reported to have three isoforms, but little is known about human Bfl-1. By reverse-transcriptase polymerase chain reaction analysis, we have identified Bfl-1S (short form), an alternative splice variant of Bfl-1. The Bfl-1S primary sequence contains four conserved Bcl-2 homology (BH) domains and a positive-charged C-terminus containing KKRK amino acids. The expression of Bfl-1S mRNA was detected predominantly in normal lymph nodes and in B-lymphoid leukemia cells. Confocal microscopic analysis using green fluorescence protein fusion proteins demonstrated that Bfl-1S is localized in the nucleus by its C-terminus as an intrinsic nuclear localization sequence. Bfl-1S acts as an antiapoptotic agent in coexpression experiments with Bax, a proapoptotic molecule. The expression of Bfl-1S provided significant resistance against staurosporine (STS) treatments in Molt-4 human T-leukemia cells. Bfl-1S also significantly inhibited the cleavage of Bid, and of caspases 3 and 8 against STS treatment. These results indicate that Bfl-1S is a novel human Bcl-2 family member that possesses antiapoptotic function.
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Affiliation(s)
- Jae-Kyun Ko
- Department of Pathology, Tumor Immunity Medical Research Center and Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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27
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Abstract
Multiple chromatin modifying proteins and multisubunit complexes have been characterized in recent years. Histone acetyltransferase (HAT) activities have been the most thoroughly studied, both biochemically and functionally. This review sums up the current knowledge on a specific group of proteins that is extremely well conserved throughout evolution, the MYST family of histone acetyltransferases. These proteins play critical roles in various nuclear functions and the control of cell proliferation.
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Affiliation(s)
- R T Utley
- Laval University Cancer Research Center, Hôtel-Dieu de Québec (CHUQ), 11 Côte du Palais, Quebec City, QC G1R 2J6, Canada
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28
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Hara Y, Zheng Z, Evans SC, Malatjalian D, Riddell DC, Guernsey DL, Wang LD, Riabowol K, Casson AG. ING1 and p53 tumor suppressor gene alterations in adenocarcinomas of the esophagogastric junction. Cancer Lett 2003; 192:109-16. [PMID: 12637159 DOI: 10.1016/s0304-3835(02)00635-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The aim of this study was to characterize molecular alterations of the recently reported candidate tumor suppressor gene, ING1, and to explore the relationship between ING1 and p53 in a well-defined series of adenocarcinomas of the esophagogastric junction (AdEGJ). Polymerase chain reaction (PCR)-based assays were used to characterize ING1 and p53 alterations, relative to histologically normal esophageal mucosa. Two tumors were found to have ING1 mutations: one novel missense mutation (AGC(Ser)-->ATC(Ile)) at codon 147, and one silent mutation (TCG(Ser)-->TCA(Ser)) at codon 173. Reduced expression of the two major alternatively spliced ING1 messenger RNA variants, p47(ING1a) and p33(ING1b) was variable, but was reduced (1.2-10-fold) in 12 of 19 AdEGJs compared to normal esophageal epithelium. No association between p53 and ING1 alterations was apparent. We conclude that reduced ING1 expression is frequently associated with AdEGJ tumorigenesis, further supporting its role as a tumor suppressor gene, and that ING1 expression is independent of p53 status.
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Affiliation(s)
- Yasuo Hara
- Departments of Biochemistry, Molecular Biology and Oncology, University of Calgary, Calgary, Alberta T2N 1N2, Canada
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29
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Breyne P, Dreesen R, Vandepoele K, De Veylder L, Van Breusegem F, Callewaert L, Rombauts S, Raes J, Cannoot B, Engler G, Inzé D, Zabeau M. Transcriptome analysis during cell division in plants. Proc Natl Acad Sci U S A 2002; 99:14825-30. [PMID: 12393816 PMCID: PMC137503 DOI: 10.1073/pnas.222561199] [Citation(s) in RCA: 90] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2002] [Accepted: 09/16/2002] [Indexed: 11/18/2022] Open
Abstract
Using synchronized tobacco Bright Yellow-2 cells and cDNA-amplified fragment length polymorphism-based genomewide expression analysis, we built a comprehensive collection of plant cell cycle-modulated genes. Approximately 1,340 periodically expressed genes were identified, including known cell cycle control genes as well as numerous unique candidate regulatory genes. A number of plant-specific genes were found to be cell cycle modulated. Other transcript tags were derived from unknown plant genes showing homology to cell cycle-regulatory genes of other organisms. Many of the genes encode novel or uncharacterized proteins, indicating that several processes underlying cell division are still largely unknown.
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Affiliation(s)
- Peter Breyne
- Department of Plant Systems Biology, Flanders Interuniversity Institute for Biotechnology, Ghent University, K.L. Ledeganckstraat 35, Belgium
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30
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Tseng WW, Deganutti A, Chen MN, Saxton RE, Liu CD. Selective cyclooxygenase-2 inhibitor rofecoxib (Vioxx) induces expression of cell cycle arrest genes and slows tumor growth in human pancreatic cancer. J Gastrointest Surg 2002; 6:838-43; discussion 844. [PMID: 12504222 DOI: 10.1016/s1091-255x(02)00061-6] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Recent studies indicate that cyclooxygenase-2 (COX-2) is overexpressed in pancreatic adenocarcinoma and may play a critical role in this rapidly progressing form of cancer. A human pancreatic adenocarcinoma cell line, Mia PaCa-2, was incubated for 18 hours with 5 micromol/L of rofecoxib (Vioxx), a selective COX-2 inhibitor. Total RNA was isolated and gene expression analyzed by DNA microarray chips. In a separate experiment, athymic mice were orthotopically injected with 7.5 x 10(5) Mia PaCa-2 cells through a minilaparotomy. After 1 month, laparotomy was repeated to measure tumor size, and mice were randomized to receive reformulated rodent chow containing either 12.5 mg/kg/day of rofecoxib or no drug for 21 days. Tumor growth was assessed by comparing volume before and after treatment. In vitro, rofecoxib decreased gene expression of cyclin D1/PRAD1, a key component of cell cycle progression, while increasing expression of several cell cycle arrest genes, including p21/WAF1, p33/ING, GADD34, and GADD45 (P < 0.05). In vivo, tumor growth was significantly reduced in treated vs. control mice (P < 0.05). No systemic toxicity was observed in mice receiving rofecoxib. These data suggest that rofecoxib slows the growth of human pancreatic cancer through changes in gene expression that favor cell cycle arrest.
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Affiliation(s)
- William W Tseng
- Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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31
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Abstract
The ING family of proteins are involved in chromatin remodelling, and bind to and affect the activity of histone acetyltransferase, histone deacetylase, and factor acetyltransferase protein complexes. Some family members affect transcription, including the expression of p53-inducible genes such as p21 and Bax, and ING2 induces p53 acetylation on a site implicated in the regulation of p53 activity. ING1 promotes DNA repair and interacts with proliferating cell nuclear antigen, thus linking DNA repair, apoptosis and chromatin remodelling. Here, we summarize what is known about the molecular interactions of ING1 family proteins and, based on these interactions, develop a model to better understand the impact of ING proteins on multiple biological processes.
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Affiliation(s)
- Xiaolan Feng
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Calgary, 3330 Hospital Drive, NW, Calgary, Alberta, Canada T2N 4N1
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32
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Vieyra D, Loewith R, Scott M, Bonnefin P, Boisvert FM, Cheema P, Pastyryeva S, Meijer M, Johnston RN, Bazett-Jones DP, McMahon S, Cole MD, Young D, Riabowol K. Human ING1 proteins differentially regulate histone acetylation. J Biol Chem 2002; 277:29832-9. [PMID: 12015309 DOI: 10.1074/jbc.m200197200] [Citation(s) in RCA: 85] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
ING1 proteins are nuclear, growth inhibitory, and regulate apoptosis in different experimental systems. Here we show that similar to their yeast homologs, human ING1 proteins interact with proteins associated with histone acetyltransferase (HAT) activity, such as TRRAP, PCAF, CBP, and p300. Human ING1 immunocomplexes contain HAT activity, and overexpression of p33(ING1b), but not of p47(ING1a), induces hyperacetylation of histones H3 and H4, in vitro and in vivo at the single cell level. p47(ING1a) inhibits histone acetylation in vitro and in vivo and binds the histone deacetylase HDAC1. Finally, we present evidence indicating that p33(ING1b) affects the degree of physical association between proliferating cell nuclear antigen (PCNA) and p300, an association that has been proposed to link DNA repair to chromatin remodeling. Together with the finding that human ING1 proteins bind PCNA in a DNA damage-dependent manner, these data suggest that ING1 proteins provide a direct linkage between DNA repair, apoptosis, and chromatin remodeling via multiple HAT.ING1.PCNA protein complexes.
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Affiliation(s)
- Diego Vieyra
- Department of Biochemistry, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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33
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Abstract
Lung cancer is the result of molecular changes that occur in the cell, resulting in the deregulation of pathways which control normal cellular growth, differentiation, and apoptosis. Several of these pathways contain well-characterized proto-oncogenes and tumor suppressor genes which are found to be mutated or have abnormal expression patterns in lung cancer. The molecular changes that characterize lung cancer are complex, but it is known that cigarette smoking causes most squamous cell and small-cell carcinomas. However, the association between cigarette smoke and adenocarcinoma is less clear. Environmental factors, such as air pollutants, radon, and asbestos, likely contribute to the development of lung cancer. In this review, we discuss the major molecular abnormalities in lung cancer with a review of recent studies that begin to decipher the role that different tumor suppressor genes and oncogenes play in the pathogenesis of lung cancer. Also, we highlight the research that has identified new genes which may play a role in lung cancer pathogenesis or progression.
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Affiliation(s)
- Jessica A Ross
- Division of Pulmonary and Critical Care, Department of Medicine, Stanford University Medical Center, Stanford, California 94304, USA
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34
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Abstract
The majority of both spontaneous and DNA damage-induced mutations in eukaryotes result from replication processes in which DNA polymerase zeta (Polzeta) and Rev1 protein (Rev1p) play major roles. Understanding these roles is likely to provide information relevant to the origin of genetic diseases, such as cancer, and may provide new insights for their prevention. DNA Polzeta also appears to be involved in the somatic hypermutability that occurs during development of the immune response. The results from a variety of genetic and enzymological investigations have started to delineate the cellular roles of these enzymes, but a number of important issues have not yet been resolved and much remains to be learned. Questions concerning the possible existence of other subunits to these enzymes, of their possible association with one another or with other proteins, of the nature of their enzymatic activities and of the relative roles played by these and other DNA polymerases in the bypass of different kinds of DNA damage, require further investigation. Finally, very little is known about the way these enzymes are regulated and brought into play when needed.
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Affiliation(s)
- Christopher W Lawrence
- Department of Biochemistry and Biophysics, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA
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Nouman GS, Angus B, Lunec J, Crosier S, Lodge A, Anderson JJ. Comparative assessment expression of the inhibitor of growth 1 gene (ING1) in normal and neoplastic tissues. HYBRIDOMA AND HYBRIDOMICS 2002; 21:1-10. [PMID: 11991811 DOI: 10.1089/15368590252917584] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Studies have indicated that the tumor suppressor p33(ING1b) (13q33-34) interact with p53. Moreover, the association of functional protein forms of each member of the p33(ING1b)/p53 complex is essential for optimum activity of p53. The present report describes the sequencing of cDNAs corresponding to the p33(ING1b) mRNAs in a series of normal and tumor cell lines, and the production of monoclonal antibodies (MAbs) reactive with p33(ING1b). These antibodies were subsequently used to analyze p33(ING1b) expression in normal and tumor cell lines and tissues. No evidence of mutation of p33(ING1b) was found in any of the 15 tumor cell lines cDNAs studied. Our investigation of a wide range of normal tissues have shown that expression of the nuclear epitope is highly ubiquitous, whereas expression of the cytoplasmic form could be detected in only 50% of tissues studied. Considering neoplastic tissues, loss of nuclear p33(ING1b) was observed in melanoma, seminoma, papillary thyroid carcinoma, ductal breast carcinoma, and acute lymphoblastic leukemia. As with normal tissue, cytoplasmic p33(ING1b) was more restricted, being observed in around 30% of neoplastic tissues, but in melanoma, papillary thyroid carcinoma, ductal breast carcinoma, there was increased detection of cytoplasmic p33(ING1b) associated with concomitant loss of nuclear expression. These results may suggest that at least in some tumors, loss of effective p33(ING1b) function may be achieved by translocation to the cytoplasm or failure of nuclear localization.
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Affiliation(s)
- Ghassan S Nouman
- Department of Pathology, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4PH, UK
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Wagner MJ, Gogela-Spehar M, Skirrow RC, Johnston RN, Riabowol K, Helbing CC. Expression of novel ING variants is regulated by thyroid hormone in the Xenopus laevis tadpole. J Biol Chem 2001; 276:47013-20. [PMID: 11600495 DOI: 10.1074/jbc.m106965200] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The candidate tumor suppressor gene, ING1, encodes several protein isoforms as a result of alternative splicing that may possess agonistic and antagonistic roles in the control of cell proliferation and apoptosis. Recently a related gene, ING2, was isolated in human whose expression is increased in adenocarcinomas. Little is known about the cellular function and regulation of these ING family members, but the fact that ING proteins contain a plant homeodomain finger suggests that these proteins may modulate transcription factor-mediated pathways. To elucidate how ING may interact in different tissues to modulate function, we used amphibian metamorphosis as a model system in which a single stimulus, thyroid hormone (TH), initiates tissue-specific proliferation, differentiation, and apoptosis. We have isolated the first Xenopus laevis ING2 and demonstrate that transcript levels increase in response to TH treatment. We provide evidence for the existence of splice variants that are differentially expressed in tissues with different TH-induced fates. Western blots using an antibody directed against the highly conserved C-terminal end of ING proteins reveal a tissue-specific pattern of ING isoform expression in adult Xenopus tissues. Analyses of premetamorphic tadpole tissues show a TH-induced accumulation of ING proteins in tail, whereas the levels in the leg are not affected. This TH-induced accumulation is also observed in serum-free tail organ cultures and is prevented by inhibitors of tail apoptosis. Therefore, this work presents the first link between ING expression and a hormonally regulated nuclear transcription factor-mediated apoptotic response opening the possibility that ING family members may be involved in transducing the signal initiated by TH that determines cell fate.
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MESH Headings
- Alternative Splicing
- Amino Acid Sequence
- Animals
- Apoptosis
- Base Sequence
- Blotting, Northern
- Blotting, Western
- Cell Differentiation
- Cell Division
- Cell Lineage
- Cell Nucleus/metabolism
- Cloning, Molecular
- Culture Media, Serum-Free/pharmacology
- DNA, Complementary/metabolism
- Female
- Gene Library
- Genes, Tumor Suppressor
- Homeodomain Proteins/biosynthesis
- Homeodomain Proteins/genetics
- Humans
- Male
- Metamorphosis, Biological
- Mice
- Molecular Sequence Data
- Organ Culture Techniques
- Protein Isoforms
- Protein Structure, Tertiary
- RNA, Messenger/metabolism
- Receptors, Cytoplasmic and Nuclear
- Receptors, Thyroid Hormone/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Sequence Homology, Amino Acid
- Signal Transduction
- Thyroid Hormones/metabolism
- Thyroid Hormones/pharmacology
- Tissue Distribution
- Triiodothyronine/pharmacology
- Tumor Suppressor Proteins
- Xenopus
- Xenopus Proteins
- Xenopus laevis
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Affiliation(s)
- M J Wagner
- Department of Biochemistry and Microbiology, University of Victoria, Victoria, British Columbia V8W 3P6, Canada
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