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1
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Rozenberg JM, Zvereva S, Dalina A, Blatov I, Zubarev I, Luppov D, Bessmertnyi A, Romanishin A, Alsoulaiman L, Kumeiko V, Kagansky A, Melino G, Ganini C, Barlev NA. The p53 family member p73 in the regulation of cell stress response. Biol Direct 2021; 16:23. [PMID: 34749806 PMCID: PMC8577020 DOI: 10.1186/s13062-021-00307-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/12/2021] [Indexed: 12/14/2022] Open
Abstract
During oncogenesis, cells become unrestrictedly proliferative thereby altering the tissue homeostasis and resulting in subsequent hyperplasia. This process is paralleled by resumption of cell cycle, aberrant DNA repair and blunting the apoptotic program in response to DNA damage. In most human cancers these processes are associated with malfunctioning of tumor suppressor p53. Intriguingly, in some cases two other members of the p53 family of proteins, transcription factors p63 and p73, can compensate for loss of p53. Although both p63 and p73 can bind the same DNA sequences as p53 and their transcriptionally active isoforms are able to regulate the expression of p53-dependent genes, the strongest overlap with p53 functions was detected for p73. Surprisingly, unlike p53, the p73 is rarely lost or mutated in cancers. On the contrary, its inactive isoforms are often overexpressed in cancer. In this review, we discuss several lines of evidence that cancer cells develop various mechanisms to repress p73-mediated cell death. Moreover, p73 isoforms may promote cancer growth by enhancing an anti-oxidative response, the Warburg effect and by repressing senescence. Thus, we speculate that the role of p73 in tumorigenesis can be ambivalent and hence, requires new therapeutic strategies that would specifically repress the oncogenic functions of p73, while keeping its tumor suppressive properties intact.
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Affiliation(s)
- Julian M Rozenberg
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.
| | - Svetlana Zvereva
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Aleksandra Dalina
- The Engelhardt Institute of Molecular Biology, Russian Academy of Science, Moscow, Russia
| | - Igor Blatov
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Ilya Zubarev
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Daniil Luppov
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | | | - Alexander Romanishin
- School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia.,School of Life Sciences, Immanuel Kant Baltic Federal University, Kaliningrad, Russia
| | - Lamak Alsoulaiman
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia
| | - Vadim Kumeiko
- School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
| | - Alexander Kagansky
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia.,School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia
| | - Gerry Melino
- Department of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Carlo Ganini
- Department of Medicine, University of Rome Tor Vergata, Rome, Italy
| | - Nikolai A Barlev
- Cell Signaling Regulation Laboratory, Moscow Institute of Physics and Technology, Dolgoprudny, Russia. .,Institute of Cytology, Russian Academy of Science, Saint-Petersburg, Russia.
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Iscan E, Ekin U, Yildiz G, Oz O, Keles U, Suner A, Cakan-Akdogan G, Ozhan G, Nekulova M, Vojtesek B, Uzuner H, Karakülah G, Alotaibi H, Ozturk M. TAp73β Can Promote Hepatocellular Carcinoma Dedifferentiation. Cancers (Basel) 2021; 13:cancers13040783. [PMID: 33668566 PMCID: PMC7918882 DOI: 10.3390/cancers13040783] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 01/14/2021] [Accepted: 01/18/2021] [Indexed: 12/26/2022] Open
Abstract
Simple Summary Hepatocellular carcinoma (HCC) is a highly complex and heterogeneous type of cancer. Hepatocyte dedifferentiation is one of the important steps in the development of HCC. However, its molecular mechanisms are not well known. In this study, we report that transcriptionally active TAp73 isoforms are overexpressed in HCC. We also show that TAp73β suppresses the expression of the hepatocyte markers including CYP3A4, AFP, ALB, HNF4α, while increasing the expression of several cholangiocyte markers in HCC cell lines. In conclusion, this report reveals a pro-oncogenic role for TAp73β in liver cancer. Abstract Hepatocyte dedifferentiation is a major source of hepatocellular carcinoma (HCC), but its mechanisms are unknown. We explored the p73 expression in HCC tumors and studied the effects of transcriptionally active p73β (TAp73β) in HCC cells. Expression profiles of p73 and patient clinical data were collected from the Genomic Data Commons (GDC) data portal and the TSVdb database, respectively. Global gene expression profiles were determined by pan-genomic 54K microarrays. The Gene Set Enrichment Analysis method was used to identify TAp73β-regulated gene sets. The effects of TAp73 isoforms were analyzed in monolayer cell culture, 3D-cell culture and xenograft models in zebrafish using western blot, flow cytometry, fluorescence imaging, real-time polymerase chain reaction (RT-PCR), immunohistochemistry and morphological examination. TAp73 isoforms were significantly upregulated in HCC, and high p73 expression correlated with poor patient survival. The induced expression of TAp73β caused landscape expression changes in genes involved in growth signaling, cell cycle, stress response, immunity, metabolism and development. Hep3B cells overexpressing TAp73β had lost hepatocyte lineage biomarkers including ALB, CYP3A4, AFP, HNF4α. In contrast, TAp73β upregulated genes promoting cholangiocyte lineage such as YAP, JAG1 and ZO-1, accompanied with an increase in metastatic ability. Our findings suggest that TAp73β may promote malignant dedifferentiation of HCC cells.
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Affiliation(s)
- Evin Iscan
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
| | - Umut Ekin
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
| | - Gokhan Yildiz
- Department of Medical Biology, Faculty of Medicine, Karadeniz Technical University, Trabzon 61000, Turkey;
| | - Ozden Oz
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
- Izmir Bozyaka Education and Research Hospital, University of Health Sciences, Izmir 35000, Turkey
| | - Umur Keles
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
| | - Aslı Suner
- Department of Biostatistics and Medical Informatics, Faculty of Medicine, Ege University, Izmir 35000, Turkey;
| | - Gulcin Cakan-Akdogan
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, Izmir 35000, Turkey
| | - Gunes Ozhan
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
| | - Marta Nekulova
- RECAMO, Masaryk Memorial Cancer Institute, 60200 Brno, Czech Republic; (M.N.); (B.V.)
| | - Borivoj Vojtesek
- RECAMO, Masaryk Memorial Cancer Institute, 60200 Brno, Czech Republic; (M.N.); (B.V.)
| | - Hamdiye Uzuner
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
| | - Gökhan Karakülah
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
| | - Hani Alotaibi
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Izmir International Biomedicine and Genome Institute, Dokuz Eylul University, Izmir 35000, Turkey
| | - Mehmet Ozturk
- Izmir Biomedicine and Genome Center, Izmir 35000, Turkey; (E.I.); (U.E.); (O.O.); (U.K.); (G.C.-A.); (G.O.); (H.U.); (G.K.); (H.A.)
- Correspondence:
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Neskorodov YB, Mardanly SG, Chuprov-Netochin RN. The Experience of Analyzing Biological Activity of Ursodeoxycholic Acid as Part of In Silico Prediction of the Gene Expression Profile. RUSS J GENET+ 2020. [DOI: 10.1134/s1022795420100099] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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4
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Krivtsova O, Makarova A, Lazarevich N. Aberrant expression of alternative isoforms of transcription factors in hepatocellular carcinoma. World J Hepatol 2018; 10:645-661. [PMID: 30386458 PMCID: PMC6206146 DOI: 10.4254/wjh.v10.i10.645] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Revised: 06/08/2018] [Accepted: 06/28/2018] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors (TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.
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Affiliation(s)
- Olga Krivtsova
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
- M. V. Lomonosov Moscow State University, Moscow 119991, Russian
| | - Anna Makarova
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
| | - Natalia Lazarevich
- Federal State Budgetary Institution, “N. N. Blokhin Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation, Moscow 115478, Russian
- M. V. Lomonosov Moscow State University, Moscow 119991, Russian
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5
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Rodríguez N, Peláez A, Barderas R, Domínguez G. Clinical implications of the deregulated TP73 isoforms expression in cancer. Clin Transl Oncol 2017; 20:827-836. [PMID: 29230693 DOI: 10.1007/s12094-017-1802-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 11/09/2017] [Indexed: 01/24/2023]
Abstract
TP73 is a member of the TP53 family whose expression has been observed altered in most human cancers and associated with the prognosis. TP73 translates into a complex number of isoforms with both oncogenic and tumour-suppressor functions and presents a complex cross-talk with other members of the family (TP53 and TP63). In this revision, we focus on the evidence that may support TP73 variants as prognostic markers in cancer. Nowadays, most publications in this topic highlight the association between overexpression of the oncogenic variants and failure to respond to chemotherapy and/or shorter survival. In addition, we comment on the putative possibilities that the detection through a liquid biopsy of TP73 variants may provide, and finally, the significance of determining the value of the combined alteration of the TP53 family members in the clinical setting.
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Affiliation(s)
- N Rodríguez
- Servicio de Oncología Médica, Hospital Universitario La Paz, CIBERONC, Madrid, Spain
| | - A Peláez
- Servicio de Anatomía Patológica and Molecular Pathology and Therapeutic Targets Group, Hospital Universitario La Paz, IdiPAZ, Madrid, Spain
| | - R Barderas
- UFIEC, ISCIII, Majadahonda, Madrid, Spain
| | - G Domínguez
- Departamento de Medicina, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols", CSIC-Universidad Autónoma de Madrid, CIBERONC, Madrid, Spain.
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Abstract
Oncolytic virus (OV) therapy utilizes replication-competent viruses to kill cancer cells, leaving non-malignant cells unharmed. With the first U.S. Food and Drug Administration-approved OV, dozens of clinical trials ongoing, and an abundance of translational research in the field, OV therapy is poised to be one of the leading treatments for cancer. A number of recombinant OVs expressing a transgene for p53 (TP53) or another p53 family member (TP63 or TP73) were engineered with the goal of generating more potent OVs that function synergistically with host immunity and/or other therapies to reduce or eliminate tumor burden. Such transgenes have proven effective at improving OV therapies, and basic research has shown mechanisms of p53-mediated enhancement of OV therapy, provided optimized p53 transgenes, explored drug-OV combinational treatments, and challenged canonical roles for p53 in virus-host interactions and tumor suppression. This review summarizes studies combining p53 gene therapy with replication-competent OV therapy, reviews preclinical and clinical studies with replication-deficient gene therapy vectors expressing p53 transgene, examines how wild-type p53 and p53 modifications affect OV replication and anti-tumor effects of OV therapy, and explores future directions for rational design of OV therapy combined with p53 gene therapy.
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7
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Di C, Sun C, Li H, Si J, Zhang H, Han L, Zhao Q, Liu Y, Liu B, Miao G, Gan L, Liu Y. Diallyl disulfide enhances carbon ion beams-induced apoptotic cell death in cervical cancer cells through regulating Tap73 /ΔNp73. Cell Cycle 2016; 14:3725-33. [PMID: 26505313 DOI: 10.1080/15384101.2015.1104438] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Diallyl disulfide (DADS), extracted from crushed garlic by steam-distillation, has been reported to provide the anticancer activity in several cancer types. However, the effect of DADS on high-LET carbon beams - induced cell death remains unknown. Therefore, we used human cervical cancer cells to elucidate the molecular effects of this diallyl sulfide. Radiotherapy remains the mainstay of treatment, especially in advanced cervical cancer and there is still space to improve the radiosensitivity to reduce radiation dosage. In this study, we found that radiation effects evoked by high-LET carbon beam was marked by inhibition of cell viability, cell cycle arrest, significant rise of apoptotic cells, regulation of transcription factor, such as p73, as well as alterations of crucial mediator of the apoptosis pathway. We further demonstrated that pretreatment of 10 µM DADS in HeLa cells exposed to radiation resulted in decrease in cell viability and increased radiosensitivity. Additionally, cells pretreated with DADS obviously inhibited the radiation-induced G2/M phase arrest, but promoted radiation-induced apoptosis. Moreover, combination DADS and the radiation exacerbated the activation of apoptosis pathways through up-regulated ration of pro-apoptotic Tap73 to anti-apoptotic ΔNp73, and its downstream proteins, such as FASLG, and APAF1. Taken together, these results suggest that DADS is a potential candidate as radio sensitive agent for cervical cancer.
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Affiliation(s)
- Cuixia Di
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Chao Sun
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Hongyan Li
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Jing Si
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Hong Zhang
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Lu Han
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Qiuyue Zhao
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Yang Liu
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Bin Liu
- d College of Stomatology ; Lanzhou University ; Lanzhou , China
| | - Guoying Miao
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Lu Gan
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
| | - Yuanyuan Liu
- a Department of Heavy Ion Radiation Medicine ; Institute of Modern Physics; Chinese Academy of Sciences ; Lanzhou , China.,b Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences ; Lanzhou , China.,c Key Laboratory of Heavy Ion Radiation Medicine of Gansu Province ; Lanzhou , China
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8
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Engelmann D, Meier C, Alla V, Pützer BM. A balancing act: orchestrating amino-truncated and full-length p73 variants as decisive factors in cancer progression. Oncogene 2014; 34:4287-99. [PMID: 25381823 DOI: 10.1038/onc.2014.365] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 09/24/2014] [Accepted: 09/29/2014] [Indexed: 12/23/2022]
Abstract
p73 is the older sibling of p53 and mimics most of its tumor-suppressor functions. Through alternative promoter usage and splicing, the TP73 gene generates more than two dozen isoforms of which N-terminal truncated DNp73 variants have a decisive role in cancer pathogenesis as they outweigh the positive effects of full-length TAp73 and p53 in acting as a barrier to tumor development. Beyond the prevailing view that DNp73 predominantly counteract cell cycle arrest and apoptosis, latest progress indicates that these isoforms acquire novel functions in epithelial-to-mesenchymal transition, metastasis and therapy resistance. New insight into the mechanisms underlying this behavior reinforced the expectation that DNp73 variants contribute to aggressive cellular traits through both loss of wild-type tumor-suppressor activity and gain-of-function, suggesting an equally important role in cancer progression as mutant p53. In this review, we describe the novel properties of DNp73 in the invasion metastasis cascade and outline the comprehensive p73 regulatome with an emphasis on molecular processes putting TAp73 out of action in advanced tumors. These intriguing insights provoke a new understanding of the acquisition of aggressive traits by cancer cells and may help to set novel therapies for a broad range of metastatic tumors.
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Affiliation(s)
- D Engelmann
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany
| | - C Meier
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany
| | - V Alla
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany
| | - B M Pützer
- Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, Rostock, Germany
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9
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Pflaum J, Schlosser S, Müller M. p53 Family and Cellular Stress Responses in Cancer. Front Oncol 2014; 4:285. [PMID: 25374842 PMCID: PMC4204435 DOI: 10.3389/fonc.2014.00285] [Citation(s) in RCA: 192] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2014] [Accepted: 10/03/2014] [Indexed: 11/30/2022] Open
Abstract
p53 is an important tumor suppressor gene, which is stimulated by cellular stress like ionizing radiation, hypoxia, carcinogens, and oxidative stress. Upon activation, p53 leads to cell-cycle arrest and promotes DNA repair or induces apoptosis via several pathways. p63 and p73 are structural homologs of p53 that can act similarly to the protein and also hold functions distinct from p53. Today more than 40 different isoforms of the p53 family members are known. They result from transcription via different promoters and alternative splicing. Some isoforms have carcinogenic properties and mediate resistance to chemotherapy. Therefore, expression patterns of the p53 family genes can offer prognostic information in several malignant tumors. Furthermore, the p53 family constitutes a potential target for cancer therapy. Small molecules (e.g., Nutlins, RITA, PRIMA-1, and MIRA-1 among others) have been objects of intense research interest in recent years. They restore pro-apoptotic wild-type p53 function and were shown to break chemotherapeutic resistance. Due to p53 family interactions small molecules also influence p63 and p73 activity. Thus, the members of the p53 family are key players in the cellular stress response in cancer and are expected to grow in importance as therapeutic targets.
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Affiliation(s)
- Johanna Pflaum
- Department of Internal Medicine I, University Hospital Regensburg , Regensburg , Germany
| | - Sophie Schlosser
- Department of Internal Medicine I, University Hospital Regensburg , Regensburg , Germany
| | - Martina Müller
- Department of Internal Medicine I, University Hospital Regensburg , Regensburg , Germany
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10
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Abstract
P73 is a member of the p53 transcription factors family with a prominent role in neurobiology, affecting brain development as well as controlling neuronal survival. Accordingly, p73 has been identified as key player in many age-related neurodegenerative diseases, such as Alzheimer's disease, neuroAIDS and Niemann-Pick type C disease. Here we investigate possible correlations of p73 with Parkinson disease. Tyrosine hydroxylase is a crucial player in Parkinson disease being the enzyme necessary for dopamine synthesis. In this work we show that levels of tyrosine hydroxylase can be influenced by p73. We also demonstrate that p73 can protect against tyrosine hydroxylase depletion in an in vitro model of Parkinson disease.
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Affiliation(s)
- Francesca Grespi
- Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK
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11
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Zhang Y, Yan W, Jung YS, Chen X. PUMA Cooperates with p21 to Regulate Mammary Epithelial Morphogenesis and Epithelial-To-Mesenchymal Transition. PLoS One 2013; 8:e66464. [PMID: 23805223 PMCID: PMC3689819 DOI: 10.1371/journal.pone.0066464] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2013] [Accepted: 05/06/2013] [Indexed: 12/20/2022] Open
Abstract
Lumen formation is essential for mammary morphogenesis and requires proliferative suppression and apoptotic clearance of the inner cells within developing acini. Previously, we showed that knockdown of p53 or p73 leads to aberrant mammary acinus formation accompanied with decreased expression of p53 family targets PUMA and p21, suggesting that PUMA, an inducer of apoptosis, and p21, an inducer of cell cycle arrest, directly regulate mammary morphogenesis. To address this, we generated multiple MCF10A cell lines in which PUMA, p21, or both were stably knocked down. We found that morphogenesis of MCF10A cells was altered modestly by knockdown of either PUMA or p21 alone but markedly by knockdown of both PUMA and p21. Moreover, we found that knockdown of PUMA and p21 leads to loss of E-cadherin expression along with increased expression of epithelial-to-mesenchymal transition (EMT) markers. Interestingly, we found that knockdown of ΔNp73, which antagonizes the ability of wide-type p53 and TA isoform of p73 to regulate PUMA and p21, mitigates the abnormal morphogenesis and EMT induced by knockdown of PUMA or p21. Together, our data suggest that PUMA cooperates with p21 to regulate normal acinus formation and EMT.
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Affiliation(s)
- Yanhong Zhang
- Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California Davis, Davis, California, United State of America
| | - Wensheng Yan
- Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California Davis, Davis, California, United State of America
| | - Yong Sam Jung
- Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California Davis, Davis, California, United State of America
| | - Xinbin Chen
- Comparative Oncology Laboratory, Schools of Medicine and Veterinary Medicine, University of California Davis, Davis, California, United State of America
- * E-mail:
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12
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Di C, Yang L, Zhang H, Ma X, Zhang X, Sun C, Li H, Xu S, An L, Li X, Bai Z. Mechanisms, function and clinical applications of DNp73. Cell Cycle 2013; 12:1861-7. [PMID: 23708520 DOI: 10.4161/cc.24967] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
p73, has two distinct promoters, which allow the formation of two protein isoforms: full-length transactivating (TA) p73 and an N-terminally truncated p73 species (referred to as DNp73) that lacks the N-terminal transactivating domain. Although the exact cellular function of DNp73 is unclear, the high expression levels of the genes have been observed in a variety of human cancers and cancer cell lines and have been connected to pro-tumor activities. Hence the aim of this review is to summarize DNp73 expression status in cancer in the current literature. Furthermore, we also focused on recent findings of DNp73 related to the biological functions from apoptosis, chemosensitivity, radiosensitibity, differentiation, development, etc. Thus this review highlights the significance of DNp73 as a marker for disease severity in patients and as target for cancer therapy.
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Affiliation(s)
- Cuixia Di
- Department of Heavy Ion Radiation Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
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Dkhil MA, Al-Quraishy S, Delic D, Abdel-Baki AA, Wunderlich F. Testosterone-induced persistent susceptibility to Plasmodium chabaudi malaria: long-term changes of lincRNA and mRNA expression in the spleen. Steroids 2013; 78:220-7. [PMID: 23123741 DOI: 10.1016/j.steroids.2012.10.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2012] [Revised: 10/01/2012] [Accepted: 10/12/2012] [Indexed: 10/27/2022]
Abstract
Testosterone (T) is known to induce persistent susceptibility to blood-stage malaria of Plasmodium chabaudi in otherwise resistant female C57BL/6 mice, which is associated with permanent changes in mRNA expression of the liver. Here, we investigate the spleen as the major effector against blood-stage malaria for any possible T-induced long-term effects on lincRNA and mRNA expression. Female C57BL/6 mice were treated with T for 3 weeks, then T was withdrawn for 12 weeks before challenging with P. chabaudi. LincRNA and mRNA expression was examined after 12 weeks of T-withdrawal and after subsequent infections using Agilent whole mouse genome oligo microarrays. Our data show for the first time long-term effects of T on lincRNA expression evidenced directly as persistent changes after T-withdrawal for 12 weeks and indirectly as altered responsiveness of expression to P. chabaudi infections. There are 3 lincRNA-species upregulated and 10 lincRNAs downregulated by more than 2-fold (p<0.01). In addition, 11 and 10 mRNAs are persistently up- and downregulated by T, respectively. These changes remain not sustained during infections at peak parasitemia, when 15 other lincRNAs and 9 other mRNAs exhibit an altered expression. The only exception is the Tnk1-mRNA encoding the non-receptor tyrosine kinase 1 that is persistently downregulated by 0.34-fold after T-withdrawal and that becomes upregulated by 5.9-fold upon infection at peak parasitemia, suggesting an involvement of tyrosine phosphorylation by Tnk1 in mediating long-term effects of T in the spleen. The T-induced changes in splenic mRNA expression are totally different to those previously observed in the liver. Collectively, our data support the view that T induces long-term organ-specific changes in both lincRNA and mRNA expression, that presumably contribute to organ-specific dysfunctions upon infection with blood-stage malaria of P. chabaudi.
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Affiliation(s)
- Mohamed A Dkhil
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia.
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14
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Grespi F, Amelio I, Tucci P, Annicchiarico-Petruzzelli M, Melino G. Tissue-specific expression of p73 C-terminal isoforms in mice. Cell Cycle 2012; 11:4474-83. [PMID: 23159862 PMCID: PMC3552929 DOI: 10.4161/cc.22787] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
p73 is a p53 family transcription factor. Due to the presence in the 5' flanking region of two promoters, there are two N-terminal variants, TAp73, which retains a fully active transactivation domain (TA), and ΔNp73, in which the N terminus is truncated. In addition, extensive 3' splicing gives rise to at least seven distinctive isoforms; TAp73-selective knockout highlights its role as a regulator of cell death, senescence and tumor suppressor. ΔNp73-selective knockout, on the other hand, highlights anti-apoptotic function of ΔNp73 and its involvement in DNA damage response. In this work, we investigated the expression pattern of murine p73 C-terminal isoforms. By using a RT-PCR approach, we were able to detect mRNAs of all the C-terminal isoforms described in humans. We characterized their in vivo expression profile in mouse organs and in different mouse developmental stages. Finally, we investigated p73 C-terminal expression profile following DNA damage, ex vivo after primary cultures treatment and in vivo after systemic administration of cytotoxic compounds. Overall, our study first elucidates spatio-temporal expression of mouse p73 isoforms and provides novel insights on their expression-switch under triggered conditions.
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Affiliation(s)
- Francesca Grespi
- Medical Research Council, Toxicology Unit, Leicester University, Leicester, UK
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15
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Conforti F, Yang AL, Agostini M, Rufini A, Tucci P, Nicklison-Chirou MV, Grespi F, Velletri T, Knight RA, Melino G, Sayan BS. Relative expression of TAp73 and ΔNp73 isoforms. Aging (Albany NY) 2012; 4:202-5. [PMID: 22388545 PMCID: PMC3348480 DOI: 10.18632/aging.100441] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The transcription factor p73 belongs to the p53 family of tumour suppressors and similar to other family members, transcribed as different isoforms with opposing pro- and anti-apoptotic functions. Unlike p53, p73 mutations are extremely rare in cancers. Instead, the pro-apoptotic activities of transcriptionally active p73 isoforms are commonly inhibited by over-expression of the dominant negative p73 isoforms. Therefore the relative ratio of different p73 isoforms is critical for the cellular response to a chemotherapeutic agent. Here, we analysed the expression of N-terminal p73 isoforms in cell lines and mouse tissues. Our data showed that the transcriptionally competent TAp73 isoform is abundantly expressed in cancer cell lines compared to the dominant negative ΔNp73 isoform. Interestingly, we detected higher levels of ΔNp73 in some mouse tissues, suggesting that ΔNp73 may have a physiological role in these tissues.
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Affiliation(s)
- Franco Conforti
- University of Southampton, Cancer Sciences Unit, Somers Cancer Research Building, Southampton, UK
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16
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Molecular mechanisms of ursodeoxycholic acid toxicity & side effects: ursodeoxycholic acid freezes regeneration & induces hibernation mode. Int J Mol Sci 2012; 13:8882-8914. [PMID: 22942741 PMCID: PMC3430272 DOI: 10.3390/ijms13078882] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2012] [Revised: 07/03/2012] [Accepted: 07/06/2012] [Indexed: 12/14/2022] Open
Abstract
Ursodeoxycholic acid (UDCA) is a steroid bile acid approved for primary biliary cirrhosis (PBC). UDCA is reported to have “hepato-protective properties”. Yet, UDCA has “unanticipated” toxicity, pronounced by more than double number of deaths, and eligibility for liver transplantation compared to the control group in 28 mg/kg/day in primary sclerosing cholangitis, necessitating trial halt in North America. UDCA is associated with increase in hepatocellular carcinoma in PBC especially when it fails to achieve biochemical response (10 and 15 years incidence of 9% and 20% respectively). “Unanticipated” UDCA toxicity includes hepatitis, pruritus, cholangitis, ascites, vanishing bile duct syndrome, liver cell failure, death, severe watery diarrhea, pneumonia, dysuria, immune-suppression, mutagenic effects and withdrawal syndrome upon sudden halt. UDCA inhibits DNA repair, co-enzyme A, cyclic AMP, p53, phagocytosis, and inhibits induction of nitric oxide synthatase. It is genotoxic, exerts aneugenic activity, and arrests apoptosis even after cellular phosphatidylserine externalization. UDCA toxicity is related to its interference with drug detoxification, being hydrophilic and anti-apoptotic, has a long half-life, has transcriptional mutational abilities, down-regulates cellular functions, has a very narrow difference between the recommended (13 mg/kg/day) and toxic dose (28 mg/kg/day), and it typically transforms into lithocholic acid that induces DNA strand breakage, it is uniquely co-mutagenic, and promotes cell transformation. UDCA beyond PBC is unjustified.
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17
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Allocati N, Di Ilio C, De Laurenzi V. p63/p73 in the control of cell cycle and cell death. Exp Cell Res 2012; 318:1285-90. [DOI: 10.1016/j.yexcr.2012.01.023] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2011] [Accepted: 01/25/2012] [Indexed: 01/19/2023]
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Abstract
TRADD (TNFR1-associated death domain protein) was initially identified as an adaptor molecule that transduces the signal downstream of the TNFR1 (tumor necrosis factor receptor 1). TNFR1 belongs to the so-called death receptor (DR) family of receptors that depending on the context can induce either apoptosis or proliferation, as well as NF-κB and MAP kinase activation. The receptors of this group contain death domain (DD) that is necessary for the induction of apoptosis. This review summarizes the recent advances in the field of DR signaling and in particular the role of TRADD.
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Affiliation(s)
- Yelena L Pobezinskaya
- Cell and Cancer Biology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Zhang CZY, Chen GG, Merchant JL, Lai PBS. Interaction between ZBP-89 and p53 mutants and its contribution to effects of HDACi on hepatocellular carcinoma. Cell Cycle 2012; 11:322-34. [PMID: 22214764 DOI: 10.4161/cc.11.2.18758] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
ZBP-89, a zinc finger transcription factor, participates in histone deacetylases inhibitors (HDACi)-mediated growth arrest and apoptosis in cancer cells. p53 mutants may interact with ZBP-89 that transcriptionally regulates p21(Waf1) (p21). However, this interaction and its consequence in cancer treatments are poorly understood. In this study, we demonstrate that ZBP‑89 is essentially required in HDACi-mediated p21 upregulation in hepetocellular carcinoma (HCC). Overexpression of ZBP-89 protein enhanced the lethal effectiveness of Trichostatin A (TSA). p53 mutant p53(G245D), but not p53(R249S), directly bound to ZBP-89 and prevented its translocation from cytoplasm to nucleus. Furthermore, p53(G245D) was shown to have a similar pattern of subcellular localization to ZBP-89 in tissues of HCC patients in Hong Kong. Functionally, the cytoplasmic accumulation of ZBP-89 by p53(G245D) significantly abrogated the induction of p21 caused by sodium butyrate (NaB) treatment and protected cells from TSA-induced death. The activations of several apoptotic proteins, such as Bid and PARP, were involved in p53(G245D)-mediated protection. Moreover, the resistance to HDACi in p53(G245D)-expressing cells was reversed by overexpression of ZBP-89. Taken together, these data suggest a potential mechanism via which mutant p53 enables tumor cells to resist chemotherapy and, therefore, establish a plausible link between mutant p53 binding to ZBP-89 and a decreased chemosensitivity of HCC cells.
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Affiliation(s)
- Chris Z Y Zhang
- Department of Surgery, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT Hong Kong
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Sen T, Sen N, Huang Y, Sinha D, Luo ZG, Ratovitski EA, Sidransky D. Tumor protein p63/nuclear factor κB feedback loop in regulation of cell death. J Biol Chem 2011; 286:43204-13. [PMID: 22020940 DOI: 10.1074/jbc.m111.257105] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Tumor protein (TP)-p53 family members often play proapoptotic roles, whereas nuclear factor κB (NF-κB) functions as a proapoptotic and antiapoptotic regulator depending on the cellular environment. We previously showed that the NF-κB activation leads to the reduction of the TP63 isoform, ΔNp63α, thereby rendering the cells susceptible to cell death upon DNA damage. However, the functional relationship between TP63 isotypes and NF-κB is poorly understood. Here, we report that the TAp63 regulates NF-κB transcription and protein stability subsequently leading to the cell death phenotype. We found that TAp63α induced the expression of the p65 subunit of NF-κB (RELA) and target genes involved in cell cycle arrest or apoptosis, thereby triggering cell death pathways in MCF10A cells. RELA was shown to concomitantly modulate specific cell survival pathways, making it indispensable for the TAp63α-dependent regulation of cell death. We showed that TAp63α and RELA formed protein complexes resulted in their mutual stabilization and inhibition of the RELA ubiquitination. Finally, we showed that TAp63α directly induced RelA transcription by binding to and activating of its promoter and, in turn, leading to activation of the NF-κB-dependent cell death genes. Overall, our data defined the regulatory feedback loop between TAp63α and NF-κB involved in the activation of cell death process of cancer cells.
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Affiliation(s)
- Tanusree Sen
- Departments of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA
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Soldevilla B, Díaz R, Silva J, Campos-Martín Y, Muñoz C, García V, García JM, Peña C, Herrera M, Rodriguez M, Gómez I, Mohamed N, Marques MM, Bonilla F, Domínguez G. Prognostic impact of ΔTAp73 isoform levels and their target genes in colon cancer patients. Clin Cancer Res 2011; 17:6029-39. [PMID: 21807636 DOI: 10.1158/1078-0432.ccr-10-2388] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Cumulative data support the role of ΔTAp73 variants in tumorigenic processes such as drug resistance. We evaluate the impact of TP73 isoforms and their putative target genes ABCB1, HMGB1, and CASP1 on the survival of colon cancer patients and the correlation between their expressions. EXPERIMENTAL DESIGN We determined in 77 colon cancer patients the expression of ΔEx2p73, ΔEx2/3p73, ΔNp73, TAp73, ABCB1, HMGB1, and CASP1 by quantitative real-time reverse transcriptase-PCR. Tumor characteristics, disease-free survival, and overall survival (OS) were examined in each patient. Functional experiments were carried out to check whether ectopic expression of ΔNp73 modifies the proliferation, drug resistance, migration, and invasion properties of colon tumor cells and the expression of ABCB1, HMGB1, and CASP1. RESULTS Positive correlations were observed between the expression levels of ΔTAp73 variants and HMGB1. Furthermore, a trend was observed for ABCB1. Overexpression of ΔEx2/3p73 and ΔNp73 isoforms was significantly associated with advanced stages (P = 0.04 and P = 0.03, respectively) and predicted shortened OS (P = 0.04 and P = 0.05, respectively). High levels of ABCB1 and HMGB1 were associated with shorter OS (P = 0.04 and P = 0.05, respectively). Multivariate analysis showed that, in addition to the tumor stage, ABCB1 and HMGB1 had independent relationships with OS (P = 0.008). Ectopic expression of ΔNp73 was associated with an increase in proliferation and drug resistance. CONCLUSIONS The positive correlation between ΔTAp73 variants and HMGB1 and ABCB1 expression supports them as TP73 targets. The fact that upregulation of ΔTAp73 isoforms was associated with shortened OS, increase in proliferation, and drug resistance confirms their oncogenic role and plausible value as prognostic markers. ABCB1 and HMGB1, putative ΔTAp73 target genes, strongly predict OS in an independent manner, making clear the importance of studying downstream TP73 targets that could predict the outcome of colon cancer patients better than ΔTAp73 variants themselves do.
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Affiliation(s)
- Beatriz Soldevilla
- Servicio de Oncología Médica, Hospital Universitario Puerta de Hierro Majadahonda, Departamento de Medicina, Universidad Autónoma de Madrid, Madrid, Spain
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Pérez-Losada J, Sanchez-Garcia I. New functions for the Snail family of transcription factors: Two-faced proteins. Cell Cycle 2010; 9:2706-8. [PMID: 20676033 PMCID: PMC3233522 DOI: 10.4161/cc.9.14.12322] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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