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Hu S, Guo W, Shen Y. Potential link between the nerve injury-induced protein (Ninjurin) and the pathogenesis of endometriosis. Int Immunopharmacol 2023; 114:109452. [PMID: 36446236 DOI: 10.1016/j.intimp.2022.109452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 10/29/2022] [Accepted: 11/10/2022] [Indexed: 11/27/2022]
Abstract
Endometriosis remains a widespread but severe gynecological disease in women of reproductive age, with an unknown etiology and few treatment choices. The menstrual reflux theory is largely accepted as the underlying etiology but does not explain the morbidity or unpleasant pain sensations of endometriosis. The neurological and immune systems are both involved in pain mechanisms of endometriosis, and interlinked through a complex combination of cytokines and neurotransmitters. Numerous pieces of evidence suggest that the nerve injury-inducible protein, Ninjurin, is actively expressed in endometriosis lesions, which contributes to the etiology and development of endometriosis. It may be explored in the future as a novel therapeutic target. The aim of the present review was to elucidate the multifaceted role of Ninjurin. Furthermore, we summarize the association of Ninjurin with the pain mechanism of endometriosis and outline the future research directions. A novel therapeutic pathway can be discovered based on the potential pathogenic variables.
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Affiliation(s)
- Sijian Hu
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weina Guo
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yi Shen
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Makgoo L, Mosebi S, Mbita Z. Molecular Mechanisms of HIV Protease Inhibitors Against HPV-Associated Cervical Cancer: Restoration of TP53 Tumour Suppressor Activities. Front Mol Biosci 2022; 9:875208. [PMID: 35620479 PMCID: PMC9127998 DOI: 10.3389/fmolb.2022.875208] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022] Open
Abstract
Cervical cancer is a Human Papilloma virus-related disease, which is on the rise in a number of countries, globally. Two essential oncogenes, E6 and E7, drive cell transformation and cancer development. These two oncoproteins target two of the most important tumour suppressors, p53 and pRB, for degradation through the ubiquitin ligase pathway, thus, blocking apoptosis activation and deregulation of cell cycle. This pathway can be exploited for anticancer therapeutic interventions, and Human Immunodeficiency Virus Protease Inhibitors (HIV-PIs) have attracted a lot of attention for this anticancer drug development. HIV-PIs have proven effective in treating HPV-positive cervical cancers and shown to restore impaired or deregulated p53 in HPV-associated cervical cancers by inhibiting the 26S proteasome. This review will evaluate the role players, such as HPV oncoproteins involved cervical cancer development and how they are targeted in HIV protease inhibitors-induced p53 restoration in cervical cancer. This review also covers the therapeutic potential of HIV protease inhibitors and molecular mechanisms behind the HIV protease inhibitors-induced p53-dependent anticancer activities against cervical cancer.
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Affiliation(s)
- Lilian Makgoo
- Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Sovenga, South Africa
| | - Salerwe Mosebi
- Department of Life and Consumer Sciences, University of South Africa, Florida, South Africa
| | - Zukile Mbita
- Department of Biochemistry, Microbiology and Biotechnology, University of Limpopo, Sovenga, South Africa
- *Correspondence: Zukile Mbita,
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Liu K, Wang Y, Li H. The Role of Ninjurin1 and Its Impact beyond the Nervous System. Dev Neurosci 2021; 42:159-169. [PMID: 33657559 DOI: 10.1159/000512222] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 10/09/2020] [Indexed: 11/19/2022] Open
Abstract
Ninjurin1 (Ninj1) is a double-transmembrane cell surface protein that could promote nerve regeneration in the process of the peripheral nervous system injury and repairment. Nonetheless, the accurate function of Ninj1 in the central nervous system and outside the nervous system is not completely clear. According to the recent studies, we found that Ninj1 is also aberrantly expressed in various pathophysiological processes in vivo, including inflammation, tumorigenesis, and vascular, bone, and muscle homeostasis. These findings suggest that Ninj1 may play an influential role during these pathophysiological processes. Our review summarizes the diverse roles of Ninj1 in multiple pathophysiological processes inside and outside the nervous system. Ninj1 should be considered as an important and novel therapeutic target in certain diseases, such as inflammatory diseases and ischemic diseases. Our study provided a better understanding of Ninj1 in different pathophysiological processes and thereby provided the theoretical support for further research.
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Affiliation(s)
- Ke Liu
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Wang
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongge Li
- Department of Neurology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China,
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Salari Fanoodi T, Motalleb G, Yegane Moghadam A, Talaee R. p21 Gene Expression Evaluation in Esophageal Cancer Patients. Gastrointest Tumors 2015. [DOI: 10.1159/000441901] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Banerjee S, Lu J, Cai Q, Sun Z, Jha HC, Robertson ES. EBNA3C augments Pim-1 mediated phosphorylation and degradation of p21 to promote B-cell proliferation. PLoS Pathog 2014; 10:e1004304. [PMID: 25121590 PMCID: PMC4133388 DOI: 10.1371/journal.ppat.1004304] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2014] [Accepted: 06/28/2014] [Indexed: 12/11/2022] Open
Abstract
Epstein–Barr virus (EBV), a ubiquitous human herpesvirus, can latently infect the human population. EBV is associated with several types of malignancies originating from lymphoid and epithelial cell types. EBV latent antigen 3C (EBNA3C) is essential for EBV-induced immortalization of B-cells. The Moloney murine leukemia provirus integration site (PIM-1), which encodes an oncogenic serine/threonine kinase, is linked to several cellular functions involving cell survival, proliferation, differentiation, and apoptosis. Notably, enhanced expression of Pim-1 kinase is associated with numerous hematological and non-hematological malignancies. A higher expression level of Pim-1 kinase is associated with EBV infection, suggesting a crucial role for Pim-1 in EBV-induced tumorigenesis. We now demonstrate a molecular mechanism which reveals a direct role for EBNA3C in enhancing Pim-1 expression in EBV-infected primary B-cells. We also showed that EBNA3C is physically associated with Pim-1 through its amino-terminal domain, and also forms a molecular complex in B-cells. EBNA3C can stabilize Pim-1 through abrogation of the proteasome/Ubiquitin pathway. Our results demonstrate that EBNA3C enhances Pim-1 mediated phosphorylation of p21 at the Thr145 residue. EBNA3C also facilitated the nuclear localization of Pim-1, and promoted EBV transformed cell proliferation by altering Pim-1 mediated regulation of the activity of the cell-cycle inhibitor p21/WAF1. Our study demonstrated that EBNA3C significantly induces Pim-1 mediated proteosomal degradation of p21. A significant reduction in cell proliferation of EBV-transformed LCLs was observed upon stable knockdown of Pim-1. This study describes a critical role for the oncoprotein Pim-1 in EBV-mediated oncogenesis, as well as provides novel insights into oncogenic kinase-targeted therapeutic intervention of EBV-associated cancers. The oncogenic serine/threonine kinase Pim-1 is upregulated in a number of human cancers including lymphomas, gastric, colorectal and prostate carcinomas. EBV nuclear antigen 3C (EBNA3C) is essential for EBV-induced transformation of human primary B-lymphocytes. Our current study revealed that EBNA3C significantly enhances Pim-1 kinase expression at both the transcript and protein levels. EBNA3C also interacts with Pim-1 and can form a complex in EBV-transformed cells. Moreover, EBNA3C increases nuclear localization of Pim-1 and stabilizes Pim-1 protein levels by inhibiting its poly-ubiquitination. Additionally, EBNA3C augments Pim-1 mediated phosphorylation of p21 and its proteosomal degradation. Stable knockdown of Pim-1 using si-RNA showed a significant decrease in proliferation of EBV transformed lymphoblastoid cell lines and subsequent induction of apoptosis by triggering the intrinsic apoptotic pathway. Therefore, our study demonstrated a new mechanism by which the oncogenic Pim-1 kinase targeted by EBV latent antigen 3C can inhibit p21 function, and is therefore a potential therapeutic target for the treatment of EBV-associated malignancies.
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Affiliation(s)
- Shuvomoy Banerjee
- Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Jie Lu
- Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Qiliang Cai
- Key Laboratory of Molecular Medical Virology (Ministries of Education and Health), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, People's Republic of China
| | - Zhiguo Sun
- Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Hem Chandra Jha
- Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
| | - Erle S. Robertson
- Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America
- * E-mail:
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Ajay AK, Upadhyay AK, Singh S, Vijayakumar MV, Kumari R, Pandey V, Boppana R, Bhat MK. Cdk5 phosphorylates non-genotoxically overexpressed p53 following inhibition of PP2A to induce cell cycle arrest/apoptosis and inhibits tumor progression. Mol Cancer 2010; 9:204. [PMID: 20673369 PMCID: PMC2922192 DOI: 10.1186/1476-4598-9-204] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2010] [Accepted: 07/31/2010] [Indexed: 01/12/2023] Open
Abstract
Background p53 is the most studied tumor suppressor and its overexpression may or may not cause cell death depending upon the genetic background of the cells. p53 is degraded by human papillomavirus (HPV) E6 protein in cervical carcinoma. Several stress activated kinases are known to phosphorylate p53 and, among them cyclin dependent kinase 5 (Cdk5) is one of the kinase studied in neuronal cell system. Recently, the involvement of Cdk5 in phosphorylating p53 has been shown in certain cancer types. Phosphorylation at specific serine residues in p53 is essential for it to cause cell growth inhibition. Activation of p53 under non stress conditions is poorly understood. Therefore, the activation of p53 and detection of upstream kinases that phosphorylate non-genotoxically overexpressed p53 will be of therapeutic importance for cancer treatment. Results To determine the non-genotoxic effect of p53; Tet-On system was utilized and p53 inducible HPV-positive HeLa cells were developed. p53 overexpression in HPV-positive cells did not induce cell cycle arrest or apoptosis. However, we demonstrate that overexpressed p53 can be activated to upregulate p21 and Bax which causes G2 arrest and apoptosis, by inhibiting protein phosphatase 2A. Additionally, we report that the upstream kinase cyclin dependent kinase 5 interacts with p53 to phosphorylate it at Serine20 and Serine46 residues thereby promoting its recruitment on p21 and bax promoters. Upregulation and translocation of Bax causes apoptosis through intrinsic mitochondrial pathway. Interestingly, overexpressed activated p53 specifically inhibits cell-growth and causes regression in vivo tumor growth as well. Conclusion Present study details the mechanism of activation of p53 and puts forth the possibility of p53 gene therapy to work in HPV positive cervical carcinoma.
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Affiliation(s)
- Amrendra K Ajay
- National Centre for Cell Science, NCCS Complex, Ganeshkhind, Pune - 411007, India
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Abstract
One of the main engines that drives cellular transformation is the loss of proper control of the mammalian cell cycle. The cyclin-dependent kinase inhibitor p21 (also known as p21WAF1/Cip1) promotes cell cycle arrest in response to many stimuli. It is well positioned to function as both a sensor and an effector of multiple anti-proliferative signals. This Review focuses on recent advances in our understanding of the regulation of p21 and its biological functions with emphasis on its p53-independent tumour suppressor activities and paradoxical tumour-promoting activities, and their implications in cancer.
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Affiliation(s)
- Tarek Abbas
- Department of Biochemistry and Molecular Genetics, University of Virginia, School of Medicine, 1340 Jefferson Park Avenue, Charlottesville, VA 22908, USA.
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Chung YL, Lee MY, Horng CF, Jian JJM, Cheng SH, Tsai SY, Hsieh CI, Yen LK, Lin CY. Use of combined molecular biomarkers for prediction of clinical outcomes in locally advanced tonsillar cancers treated with chemoradiotherapy alone. Head Neck 2009; 31:9-20. [PMID: 18767174 DOI: 10.1002/hed.20913] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Environmental exposures to tobacco, alcohol, human papillomavirus (HPV) and/or Epstein-Barr virus (EBV), all of which can perturb multiple cell cycle proteins or tumor suppressors, have been implicated in the pathogenesis of different subsets of head and neck cancers. The aim of this study was to investigate to which extent the virus infection by itself, and/or the altered cell cycle proteins, contributes to prognosis in locally advanced tonsillar squamous cell carcinomas (TSCCs) treated with concurrent chemoradiotherapy (CCRT) alone. METHODS Serial tumor tissue arrays from archival samples were tested for the presence of HPV genome integration or EBV episome by means of DNA sequencing, real-time polymerase chain reaction (PCR), and in situ hybridization. Alterations of cell cycle proteins (p53, pRb, and p21) were evaluated by immunohistochemical staining. The association of viral presence with altered cell cycle proteins was correlated to clinical outcomes. RESULTS Of the 46 patients with the same T2N2bM0 stage IVA among consecutive patients with TSCC, 23 (50%) had integrated HPV DNA and only 1 (2%) had EBV episome. The HPV types detected were almost all HPV-16. A reduced expression pattern of p53, pRb, and p21 was noted in HPV-positive tumors, and the incremental number of alterations in the 3 proteins was significantly associated with HPV-negative tumors. The presence or absence of HPV together with the number of altered expression of the 3 cell cycle markers resulted in further identification of 4 biologically and clinically distinct subgroups with different outcomes after CCRT. CONCLUSIONS Use of combined biomarkers of oncogenic HPV and tumor suppressors of p53, pRb, and p21 in advanced TSCC provides prognostic molecular classification superior to the TNM stage system and identifies low-risk patients for organ preservation by CCRT alone and high-risk patients who might benefit from planned tonsillectomy and neck dissection before or after CCRT.
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Affiliation(s)
- Yih-Lin Chung
- Department of Radiation Oncology, Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan.
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Min LJ, Mogi M, Iwai M, Horiuchi M. Signaling mechanisms of angiotensin II in regulating vascular senescence. Ageing Res Rev 2009; 8:113-21. [PMID: 19162241 DOI: 10.1016/j.arr.2008.12.002] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2008] [Revised: 12/10/2008] [Accepted: 12/16/2008] [Indexed: 02/07/2023]
Abstract
Angiotensin (Ang) II, the major effector of the rennin-angiotensin-aldosterone system (RAAS), has multiple functions in regulating cardiovascular hemodynamics and structure. Recent evidence strongly supports that Ang II promotes the onset and progression of vascular senescence, which is associated with vascular functional and structural changes, contributing to age-related vascular diseases. The vast majority of the cardiovascular actions of Ang II, including vascular senescence, are mediated by the Ang II type-1 (AT(1)) receptor. Similar to its growth-promoting process, the signaling mechanisms of AT(1) receptor-mediated vascular senescence-promoting effects involve activation of small G-protein Ras such as Ki-ras2A, mitogen-activated protein kinases (MAPK) such as extracellular signal-regulated kinase 1/2, and transcription factors including nuclear factor (NF)-kappaB and activator protein (AP)-1, and increased generation of reactive oxygen species. Moreover, AT(1) receptor stimulation has been suggested to inactivate cyclin-dependent kinase complexes by up-regulation of cell cycle regulators such as p53 and p21, resulting in cellular senescence. Furthermore, the interaction between Ang II and aldosterone (Aldo) in their contribution to cardiovascular pathophysiology has been highlighted. Aldo can interact with Ang II signaling via a genomic mechanism mediated by the mineralocorticoid receptor (MR). Aldo via MR couples with the AT(1) receptor to elicit the Ras/NF-kappaB, AP-1/p53/p21 pathway involving oxidative stress, leading to synergistic promotion of vascular senescence. Although the precise mechanisms controlling cellular senescence are currently poorly understood, this article reviews recent findings on the signaling mechanisms elicited by RAAS from the perspective of AT(1) receptor blockers and/or MR blockers in the treatment of age-related vascular diseases.
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Posttranscriptional induction of p21Waf1 mediated by ectopic p16INK4 in human diploid fibroblast. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200703010-00011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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11
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Posttranscriptional induction of p21Waf1 mediated by ectopic p16INK4 in human diploid fibroblast. Chin Med J (Engl) 2007. [DOI: 10.1097/00029330-200703010-00012] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Hampson L, Kitchener HC, Hampson IN. Specific HIV Protease Inhibitors Inhibit the Ability of Hpv16 E6 to Degrade P53 and Selectively Kill E6-Dependent Cervical Carcinoma Cells In Vitro. Antivir Ther 2005. [DOI: 10.1177/135965350601100607] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Although HIV protease inhibitor (PI) drugs predominantly target HIV proteases 1 and 2, it is also known that part of their efficacy is due to selective inhibition of the proteasome. The pathogenicity of high-risk human papilloma virus (HPV) is dependent on expression of viral E6 proteins which inappropriately activate the 26S proteasome to degrade p53 and other cellular proteins that are detrimental to viral replication. Comparison of the ability of the PIs indinavir, ritonavir, amprenavir, lopinavir, atazanavir, nelfinavir and saquinavir to inhibit E6-mediated proteasomal degradation of mutant p53 in E6-transfected C33A cells showed that 15μM lopinavir, 1 mM indinavir or 125 μM ritonavir treatment for 24 h produced a stable increase in the level of nuclear p53 in these cells with minimal cell death. After 4 h exposure of HPV16+ve SiHa cells to 15 μM lopinavir, a transient increase in wild-type p53 expression was observed associated with a 7% reduction in the chymotryptic activity of the 20S proteasome and apoptosis after 24 h. Comparison of growth rates of PI treated SiHa, CaSki, C33A, C33A-E6 and non-transformed NIH/3T3 cells showed that SiHa were the most sensitive, whereas NIH/3T3 were least affected. In conclusion, these data show that specific HIV PIs such as lopinavir and possibly indinavir, can induce selective toxicity of HPV-transformed cervical carcinoma cells expressing wild-type p53 and may form the basis of a topically applied alternative to surgery for the treatment of HPV-related premalignant lesions of the cervix.
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Affiliation(s)
- Lynne Hampson
- University of Manchester Gynaecological Oncology Laboratories, Human Development, St Mary's Hospital, Manchester M13 OJH
| | - Henry C Kitchener
- University of Manchester Gynaecological Oncology Laboratories, Human Development, St Mary's Hospital, Manchester M13 OJH
| | - Ian N Hampson
- University of Manchester Gynaecological Oncology Laboratories, Human Development, St Mary's Hospital, Manchester M13 OJH
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Fan X, Liu Y, Chen JJ. Down-regulation of p21 contributes to apoptosis induced by HPV E6 in human mammary epithelial cells. Apoptosis 2005; 10:63-73. [PMID: 15711923 DOI: 10.1007/s10495-005-6062-y] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Infection with human papillomaviruses (HPV) is strongly associated with the development of cervical cancer. The HPV E6 gene is essential for the oncogenic potential of HPV. E6 induces cell proliferation and apoptosis in cervical cancer precursor lesions and in cultured cells. Although induction of telomerase and inactivation of the tumor suppressor p53 play important roles for E6 to promote cell growth, the molecular basis of E6-induced apoptosis is poorly understood. While it is expected that inactivation of p53 by E6 should lead to a reduction in cellular apoptosis, numerous studies demonstrated that E6 could in fact sensitize cells to apoptosis. Understanding the mechanism of p53-independent apoptosis is of clinical significance. In the present study, we investigated the mechanism of apoptosis during E6-mediated immortalization of primary human mammary epithelial cell (HMEC). E6 by itself is sufficient to immortalize HMECs and is believed to do so at least in part by activation of telomerase. During the process of E6-mediated HMEC immortalization, an increased apoptosis was observed. Mutational analysis demonstrated that E6-induced apoptosis was distinct from its ability to promote cell proliferation, activate telomerase, or degrade p53. While the known pro-apoptotic E6 target proteins such as Bak or c-Myc did not appear to play an important role, down-regulation of the cyclin-dependent kinase inhibitor p21(Waf1/Cip1) (p21) by E6 correlated with its ability to induce apoptosis. Ectopic expression of p21 inhibited E6-induced apoptosis. Moreover, a p53 degradation defective E6 mutant was competent for p21 down-regulation and apoptosis induction. The anti-apoptotic function of p21 may not simply be the result of p21-induced growth arrest. These studies demonstrate an E6 activity to down-regulate p21 that is important for induction of apoptosis.
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Affiliation(s)
- Xueli Fan
- Department of Medicine, University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605-2324, USA
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Abstract
Infection with human papillomaviruses is strongly associated with the development of multiple cancers including esophageal squamous cell carcinoma. The HPV E6 gene is essential for the oncogenic potential of HPV. The regulation of apoptosis by oncogene has been related to carcinogenesis closely; therefore, the modulation of E6 on cellular apoptosis has become a hot research topic recently. Inactivation of the pro-apoptotic tumor suppressor p53 by E6 is an important mechanism by which E6 promotes cell growth; it is expected that inactivation of p53 by E6 should lead to a reduction in cellular apoptosis, numerous studies showed that E6 could in fact sensitize cells to apoptosis. The molecular basis for apoptosis modulation by E6 is poorly understood. In this article, we will present an overview of observations and current understanding of molecular basis for E6-induced apoptosis.
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Affiliation(s)
- Ting-Ting Li
- Institute of Gastroenterology, 15 West Changle Road, Xijing Hospital Xi'an 710032, Shaanxi Province, China
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Toyama T, Sasaki Y, Horimoto M, Iyoda K, Yakushijin T, Ohkawa K, Takehara T, Kasahara A, Araki T, Hori M, Hayashi N. Ninjurin1 increases p21 expression and induces cellular senescence in human hepatoma cells. J Hepatol 2004; 41:637-43. [PMID: 15464245 DOI: 10.1016/j.jhep.2004.06.027] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2004] [Revised: 06/09/2004] [Accepted: 06/25/2004] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS Ninjurin1 is a novel adhesion molecule that has a role in promoting nerve regeneration. Although ninjurin1 is ubiquitously expressed in various human tissues, including the liver, the biologic functions of ninjurin1 in tissues other than the nervous system remain unknown. The aim of this study was to investigate the function of ninjurin1 in hepatocytes. METHODS The effect of ninjurin1 overexpression was examined in Huh-7 hepatoma cells. Ninjurin1 expression was examined by Western blot in human hepatocellular carcinoma tissues as well as their adjacent liver tissues. RESULTS Ninjurin1-overexpressing clones exhibited strong growth inhibition due to G1 cell cycle arrest, which is associated with a posttranscriptional increase in p21WAF1/Cip1, a decrease of cyclin-dependent kinase 2 activity and the hypophosphorylation of Rb. The ninjurin1-overexpressing clones had increased senescence-associated beta-galactosidase activity and autofluorescent pigment, characteristic features of cellular senescence. The levels of ninjurin1 expression were higher in hepatocellular carcinoma tissues than those in adjacent liver tissues. CONCLUSIONS The present study provides the first evidence that ninjurin1 is able to induce the senescence program. Ninjurin1 may be involved in the regulation of cellular senescence in the liver during carcinogenesis.
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Affiliation(s)
- Takashi Toyama
- Department of Internal Medicine and Therapeutics, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
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Li W, Thompson CH, Cossart YE, O'Brien CJ, McNeil EB, Scolyer RA, Rose BR. The expression of key cell cycle markers and presence of human papillomavirus in squamous cell carcinoma of the tonsil. Head Neck 2004; 26:1-9. [PMID: 14724900 DOI: 10.1002/hed.10335] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Chemical carcinogens induce squamous cell carcinoma (SCC) of the head and neck by targeting the p53 and the retinoblastoma (pRb) pathways. Human papillomavirus (HPV) might have an etiologic role in these cancers at particular sites. Few studies have compared cell cycle protein expression in HPV-positive and HPV-negative tumors in this region. METHODS Fifty tonsil SCCs were analyzed for HPV by PCR and for expression of cell cycle proteins (p53, pRb, p16(INK4A), p21(CIP1/WAF1), p27(KIP1), and cyclinD1) by immunohistochemistry. RESULTS HPV was present in 42%; almost all were type 16. There were statistical associations between HPV positivity and reduced expression of pRb and cyclinD1, overexpression of p16, and younger patient age. Tumor with down-regulated p27 tended to have down-regulated pRb and p21. CONCLUSIONS HPV-positive tonsil SCCs have distinct molecular pathways. Their association with younger patient age suggests that they are biologically distinct from HPV-negative tumors.
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Affiliation(s)
- Wei Li
- Sydney Head and Neck Cancer Institute, PO Box M 142, Missenden Road, Camperdown, NSW 2050, Australia
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Minamino T, Miyauchi H, Yoshida T, Tateno K, Kunieda T, Komuro I. Vascular cell senescence and vascular aging. J Mol Cell Cardiol 2004; 36:175-83. [PMID: 14871544 DOI: 10.1016/j.yjmcc.2003.11.010] [Citation(s) in RCA: 100] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2003] [Revised: 11/15/2003] [Accepted: 11/17/2003] [Indexed: 10/26/2022]
Abstract
Vascular cells have a finite lifespan when cultured in vitro and eventually enter an irreversible growth arrest called "cellular senescence". A number of genetic animal models carrying targeted disruption of the genes that confer the protection against senescence in vitro have been reported to exhibit the phenotypes of premature aging. Similar mutations have been found in the patients with premature aging syndromes. Many of the changes in senescent vascular cell behavior are consistent with the changes seen in age-related vascular diseases. We have demonstrated the presence of senescent vascular cells in human atherosclerotic lesions but not in non-atherosclerotic lesions. Moreover, these cells express increased levels of pro-inflammatory molecules and decreased levels of endothelial nitric oxide synthase, suggesting that cellular senescence in vivo contributes to the pathogenesis of human atherosclerosis. One widely discussed hypothesis of senescence is the telomere hypothesis. An increasing body of evidence has established the critical role of the telomere in vascular cell senescence. Another line of evidence suggests that telomere-independent mechanisms are also involved in vascular cell senescence. Activation of Ras, an important signaling molecule involved in atherogenic stimuli, induces vascular cell senescence and thereby promotes vascular inflammation in vitro and in vivo. It is possible that mitogenic-signaling pathways induce telomere-dependent and telomere-independent senescence, which results in vascular dysfunction. Further understanding of the mechanism underlying cellular senescence will provide insights into the potential of antisenescence therapy for vascular aging.
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Affiliation(s)
- Tohru Minamino
- Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan
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18
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Halkidou K, Gnanapragasam VJ, Mehta PB, Logan IR, Brady ME, Cook S, Leung HY, Neal DE, Robson CN. Expression of Tip60, an androgen receptor coactivator, and its role in prostate cancer development. Oncogene 2003; 22:2466-77. [PMID: 12717424 DOI: 10.1038/sj.onc.1206342] [Citation(s) in RCA: 162] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Prostate cancer (CaP) is initially androgen sensitive and responsive to hormone ablation therapy. However, cancer growth recurs despite androgen deprivation in the majority of cases of advanced disease. The molecular basis of this progression still remains unknown. The significance of androgen receptor (AR) coactivator proteins in this androgen-dependent malignancy is only beginning to emerge. In the present study, we examined the role of Tat interactive protein, 60 kDa (Tip60), an AR coactivator, in CaP progression. In hormone refractory CaP biopsies, we observed a nuclear accumulation of Tip60 expression in contrast to a more diffuse distribution pattern observed in benign prostate hyperplasia and primary CaP. Furthermore, in both the prostate xenograft model CWR22 and the LNCaP CaP cell line, we observed that androgen withdrawal promoted upregulation of Tip60 as well as nuclear accumulation. In contrast, androgen exposure resulted in decreased Tip60 expression that was more closely linked to a cytoplasmic presence. Chromatin immunoprecipitation analysis revealed Tip60's recruitment to the PSA gene promoter in both androgen-dependent and -independent cell lines. Thus, in vitro and in vivo data support a possible role for Tip60 in the molecular pathway leading to the development of androgen-independent CaP following long-term androgen deprivation therapy.
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Affiliation(s)
- Kalipso Halkidou
- 1Prostate Research Group, School of Surgical and Reproductive Sciences, University of Newcastle, Framlington Place, Newcastle upon Tyne NE2 4HH, UK
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19
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Chen B, Athanasiou M, Gu Q, Blair DG. Drm/Gremlin transcriptionally activates p21(Cip1) via a novel mechanism and inhibits neoplastic transformation. Biochem Biophys Res Commun 2002; 295:1135-41. [PMID: 12135612 DOI: 10.1016/s0006-291x(02)00828-8] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Drm/Gremlin, a member of the Dan family of BMP antagonists, is known to function in early embryonic development, but is also expressed in a tissue-specific fashion in adults and is significantly downregulated in transformed cells. In this report, we demonstrate that overexpression of Drm in the tumor-derived cell lines Daoy (primitive neuroectodermal) and Saos-2 (osteoblastic), either under ecdysone-inducible or constitutive promoters, significantly inhibits tumorigenesis. Furthermore, Drm overexpression in these cells increases the level of p21(Cip1) protein and reduces the level of phosphorylated p42/44 MAP kinase. Finally, our data indicate that Drm can induce p21(Cip1) transcriptionally via a novel pathway that is independent of p53 and the p38 and p42/44 MAP kinases. These results provide evidence that Drm can function as a novel transformation suppressor and suggest that this may occur through its affect on the levels of p21(Cip1) and phosphorylated p42/44 MAPK.
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Affiliation(s)
- Bo Chen
- Basic Research Laboratory, National Cancer Institute at Frederick, Bldg. 469, Rm. 102, Frederick, MD 21702-1201, USA
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20
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21
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Shou J, Ali-Osman F, Multani AS, Pathak S, Fedi P, Srivenugopal KS. Human Dkk-1, a gene encoding a Wnt antagonist, responds to DNA damage and its overexpression sensitizes brain tumor cells to apoptosis following alkylation damage of DNA. Oncogene 2002; 21:878-89. [PMID: 11840333 DOI: 10.1038/sj.onc.1205138] [Citation(s) in RCA: 129] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2001] [Revised: 10/09/2001] [Accepted: 10/31/2001] [Indexed: 01/05/2023]
Abstract
The human Dkk-1 (hDkk-1) gene, a transcriptional target of the p53 tumor suppressor, encodes a powerful inhibitor of the Wnt signaling pathway and regulates the spatial patterning/morphogenesis of the mammalian central nervous system. We investigated the p53-related functions of the hDkk-1 gene by studying its response to DNA damage and its modulation of apoptosis in human glioma cells. Various chemotherapeutic and other agents that induce DNA adducts and compromise its integrity (1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), cisplatin, H(2)O(2) and UV rays) enhanced the expression of hDkk-1 significantly. The damage-induced increase in hDkk-1 mRNA levels occurred in many human tumor cell lines, irrespective of their p53 gene status. The human glioblastoma cell line, U87MG, which had undetectable hDkk-1 expression, was engineered to express moderate levels of the hDkk protein by stable transfection. The engineered cells did not show any morphological changes, but underwent marked apoptosis after ceramide treatment. Further, the DNA cross-linking drugs BCNU and cisplatin, but not the microtubule poison vincristine, induced significant cell death in U87MG/hDkk cells, and this was accompanied by altered Bcl-2/Bax expression and a reduction in the amount of telomere DNA as visualized by fluorescence in situ hybridization. These results show that hDkk-1 is a pro-apoptotic gene and suggest that it may play important roles in linking the oncogenic Wnt and p53 tumor suppressor pathways.
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MESH Headings
- Alkylation
- Antineoplastic Agents, Alkylating/pharmacology
- Apoptosis/drug effects
- Apoptosis/physiology
- Brain Neoplasms/genetics
- Brain Neoplasms/metabolism
- Brain Neoplasms/pathology
- DNA Damage
- DNA, Neoplasm/drug effects
- Drug Resistance, Neoplasm
- Gene Expression Regulation, Neoplastic/drug effects
- Genes, bcl-2
- Genes, p53
- Glioblastoma/genetics
- Glioblastoma/metabolism
- Glioblastoma/pathology
- Humans
- Hydrogen Peroxide/pharmacology
- Intercellular Signaling Peptides and Proteins
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Neoplasm Proteins/physiology
- Proteins/genetics
- Proteins/physiology
- Proto-Oncogene Proteins/antagonists & inhibitors
- Proto-Oncogene Proteins/biosynthesis
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/physiology
- Proto-Oncogene Proteins c-bcl-2/biosynthesis
- RNA, Messenger/biosynthesis
- RNA, Neoplasm/biosynthesis
- Signal Transduction/physiology
- Sphingosine/analogs & derivatives
- Sphingosine/pharmacology
- Telomere/drug effects
- Telomere/ultrastructure
- Transfection
- Tumor Cells, Cultured/metabolism
- Tumor Cells, Cultured/pathology
- Tumor Suppressor Protein p53/deficiency
- Tumor Suppressor Protein p53/physiology
- Ultraviolet Rays
- Wnt Proteins
- Zebrafish Proteins
- bcl-2-Associated X Protein
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Affiliation(s)
- Jiang Shou
- Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Road, Houston, TX 77030, USA
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22
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Schwarze SR, Shi Y, Fu VX, Watson PA, Jarrard DF. Role of cyclin-dependent kinase inhibitors in the growth arrest at senescence in human prostate epithelial and uroepithelial cells. Oncogene 2001; 20:8184-92. [PMID: 11781834 DOI: 10.1038/sj.onc.1205049] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2001] [Revised: 09/19/2001] [Accepted: 10/09/2001] [Indexed: 02/07/2023]
Abstract
Cellular senescence has been proposed to be an in vitro and in vivo block that cells must overcome in order to immortalize and become tumorigenic. To characterize these pathways, we focused on changes in the cyclin-dependent kinase inhibitors and their binding partners that underlie the cell cycle arrest at senescence. As a model, we utilized normal human prostate epithelial cell (HPEC) and human uroepithelial cell (HUC) cultures. After 30-40 population doublings cells became growth-arrested in G0/1 with a threefold decrease in Cdk2-associated activity, a point defined as pre-senescence. Temporally following this growth arrest, the cells develop a senescence morphology and express senescence-associated beta-galactosidase (SA-beta-gal). Levels of p16(INK4a) and p57(KIP2) rise in HUCs during progressive passages, whereas only p16 increases in HPEC cultures. The induced expression of p57, similar to p16, produces a senescent-like phenotype. pRB, cyclin D, p19(INK4d) and p27(KIP1) decrease in both cell types. We find that p53, p21(CIP1) and p15(INK4b) are transiently elevated in HPECs and HUCs at the pre-senescent growth arrest, then return to low proliferating levels at terminal senescence. Analysis of p53, p21(CIP1), p15(INK4b), p16(INK4a), and p57(KIP2) reveals altered expression in immortalized, non-tumorigenic HPV16 E6 and E7 prostate lines and in tumorigenic prostate cancer cells. These results indicate: (i) the existence of a subset of growth inhibiting genes elevated at the onset of the senescence, (ii) a distinct class of genes involved in the maintenance of senescence, and (iii) the frequent inactivation of these pathways during immortalization.
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Affiliation(s)
- S R Schwarze
- Department of Surgery, University of Wisconsin Comprehensive Cancer Center and the University of Wisconsin Medical School, Madison, WI 53972, USA
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23
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Abstract
Organisms with renewable tissues had to evolve mechanisms to prevent the development of cancer. One such mechanism is cellular senescence, which irreversibly arrests the growth of cells at risk for neoplastic transformation. Recent findings have revealed the complexities of the senescence phenotype and unexpected possible consequences for the organism.
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Affiliation(s)
- J Campisi
- Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA.
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Horikawa I, Parker ES, Solomon GG, Barrett JC. Upregulation of the gene encoding a cytoplasmic dynein intermediate chain in senescent human cells. J Cell Biochem 2001; 82:415-21. [PMID: 11500918 DOI: 10.1002/jcb.1169] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Normal human somatic cells, unlike cancer cells, stop dividing after a limited number of cell divisions through the process termed cellular senescence or replicative senescence, which functions as a tumor-suppressive mechanism and may be related to organismal aging. By means of the cDNA subtractive hybridization, we identified eight genes upregulated during normal chromosome 3-induced cellular senescence in a human renal cell carcinoma cell line. Among them is the DNCI1 gene encoding an intermediate chain 1 of the cytoplasmic dynein, a microtubule motor that plays a role in chromosome movement and organelle transport. The DNCI1 mRNA was also upregulated during in vitro aging of primary human fibroblasts. In contrast, other components of cytoplasmic dynein showed no significant change in mRNA expression during cellular aging. Cell growth arrest by serum starvation, contact inhibition, or gamma-irradiation did not induce the DNCI1 mRNA, suggesting its specific role in cellular senescence. The DNCI1 gene is on the long arm of chromosome 7 where tumor suppressor genes and a senescence-inducing gene for a group of immortal cell lines (complementation group D) are mapped. This is the first report that links a component of molecular motor complex to cellular senescence, providing a new insight into molecular mechanisms of cellular senescence.
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Affiliation(s)
- I Horikawa
- Laboratory of Biosystems and Cancer, Cancer and Aging Section, National Cancer Institute, Bethesda, Maryland 20892, USA.
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26
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Obata M, Imamura E, Yoshida Y, Goto J, Kishibe K, Yasuda A, Ogawa K. Resistance of primary cultured mouse hepatic tumor cells to cellular senescence despite expression of p16(Ink4a), p19(Arf), p53, and p21(Waf1/Cip1). Mol Carcinog 2001; 32:9-18. [PMID: 11568971 DOI: 10.1002/mc.1059] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Primary cultured mouse hepatic cells become senescent within a short period, although rare cells form colonies from which continuously proliferating cell lines can be established. In contrast, hepatic tumor (HT) cells show little senescence and higher colony-forming capacity. To assess this difference, we investigated p16(Ink4a)/p19(Arf)/p53/p21(Waf1/Cip1) expression in primary normal and HT cells, together with cell lines established from both. In primary normal cells, p16(Ink4a)/p19(Arf) were expressed only in association with senescence and disappeared at later stages of colony formation. In contrast, primary HT cells showed sustained p16(Ink4a)/p19(Arf) expression from the beginning. No p16(Ink4a)/p19(Arf) alterations, such as deletion, mutations, or hypermethylation, were detected in the primary HT cells, although most cell lines derived from either normal or HT cell colonies lost p16(Ink4a) or p19(Arf) expression owing to hypermethylation or homozygous deletion of p16(Ink4a)/p19(Arf). On the other hand, primary normal and HT cells and most cell lines showed constitutively elevated expression of p53/p21(Waf1/Cip1), with a further increment after ultraviolet ir-radiation, indicating a functionally normal p53 pathway. These results indicate that primary HT cells are resistant to senescence despite retaining p16(Ink4a)/p19(Arf)/p53/p21(Waf1/Cip1) expression and that loss of p16(Ink4a)/p19(Arf) function is associated only with establishment of the cell lines.
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Affiliation(s)
- M Obata
- Department of Pathology, Asahikawa Medical College, Asahikawa, Japan
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27
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Giannoudis A, Herrington CS. Differential expression of p53 and p21 in low grade cervical squamous intraepithelial lesions infected with low, intermediate, and high risk human papillomaviruses. Cancer 2000; 89:1300-7. [PMID: 11002226 DOI: 10.1002/1097-0142(20000915)89:6<1300::aid-cncr15>3.0.co;2-u] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
BACKGROUND Basal cell tetrasomy in low grade squamous intraepithelial lesions of the cervix is associated with infection by high and intermediate risk but not low risk human papillomaviruses (HPVs). It is known that the viral E6 and E7 proteins interact with p53 and p21, respectively, altering cell cycle control and leading to chromosomal instability. In this study, p53 and p21 expression was analyzed in disomic and tetrasomic low grade squamous intraepithelial lesions infected with a wide range of HPV types. METHODS HPV identification and typing was performed using both in situ hybridization and the polymerase chain reaction followed by dot blot hybridization with specific HPV probes. Interphase cytogenetic analysis using centromeric chromosomal probes also performed was to identify numeric chromosomal abnormalities. The expression of p53 and p21 was studied by immunohistochemistry using monoclonal antibodies specific for these proteins. RESULTS Increased expression of p53 and p21 was more widespread in lesions infected with low risk than with intermediate/high risk HPV types (p53, P < 0.001; p21, P < 0.01). p53 status correlated with p21 expression when analyzed according to the distribution of expression by using 3 groups, focal, regional, and diffuse (Pearson coefficient, r = 0.47, P < 0.001). In the lesions infected with intermediate/high risk HPVs, expression of p53 was significantly decreased or completely absent in tetrasomic areas, whereas expression of p21 was similar in both disomic and tetrasomic regions. CONCLUSIONS The authors' data suggest that low, intermediate, and high risk HPVs have different effects on p53 and p21 protein expression, and that the induction of numeric chromosomal abnormalities by intermediate/high risk HPVs may be related to altered expression of p53.
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Affiliation(s)
- A Giannoudis
- University of Liverpool, Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom
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Dulić V, Beney GE, Frebourg G, Drullinger LF, Stein GH. Uncoupling between phenotypic senescence and cell cycle arrest in aging p21-deficient fibroblasts. Mol Cell Biol 2000; 20:6741-54. [PMID: 10958672 PMCID: PMC86196 DOI: 10.1128/mcb.20.18.6741-6754.2000] [Citation(s) in RCA: 83] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/1999] [Accepted: 06/08/2000] [Indexed: 11/20/2022] Open
Abstract
Irreversible G(1) arrest in senescent human fibroblasts is mediated by two inhibitors of cyclin-dependent kinases (Cdks), p21(Cip1/SDI1/WAF1) and p16(Ink4A). To determine the physiological and molecular events that specifically require p21, we studied senescence in human diploid fibroblasts expressing the human papillomavirus type 16 E6 oncogene, which confers low p21 levels via enhanced p53 degradation. We show that in late-passage E6 cells, high Cdk activity drives the cell cycle, but population expansion is slowed down by crisis-like events, probably owing to defective cell cycle checkpoints. At the end of lifespan, terminal-passage E6 cells exhibited several aspects of the senescent phenotype and accumulated unphosphorylated pRb and p16. However, both replication and cyclin-Cdk2 kinase activity were still not blocked, demonstrating that phenotypic and replicative senescence are uncoupled in the absence of normal p21 levels. At this stage, E6 cells also failed to upregulate p27 and inactivate cyclin-Cdk complexes in response to serum deprivation. Eventually, irreversible G(1) arrest occurred coincident with inactivation of cyclin E-Cdk2 owing to association with p21. Similarly, when p21(-/-) mouse embryo fibroblasts reached the end of their lifespan, they had the appearance of senescent cells yet, in contrast to their wild-type counterparts, they were deficient in downregulating bromodeoxyuridine incorporation, cyclin E- and cyclin A-Cdk2 activity, and inhibiting pRb hyperphosphorylation. These data support the model that the critical event ensuring G(1) arrest in senescence is p21-dependent Cdk inactivation, while other aspects of senescent phenotype appear to occur independently of p21.
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Affiliation(s)
- V Dulić
- Centre de Recherche en Biochimie Macromoléculaire (CRBM)-Centre National de la Recherche Scientifique (CNRS), Montpellier, France.
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29
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Abstract
The limited proliferative potential of normal cells in culture has been proposed as a model for cellular aging in vivo. It is clear that cellular aging has a genetic component but epigenetic processes could also be involved. Insight gained during years of intensive study suggests cellular aging is a multi-step process and that cells possess a counting mechanism that determines the number of doublings the cells can complete. In this paper, we review evidence suggesting a role for epigenetic processes in cell senescence and discuss the possible insights that might be provided by experiments designed to induce a premature senescent like state.
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Affiliation(s)
- J Young
- Huffington Center on Aging, MS M320, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA
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