Document Detail


Anoxic fibroblasts activate a replication checkpoint that is bypassed by E1a.
MedLine Citation:
PMID:  14645516     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Little is known about cell cycle regulation in hypoxic cells, despite its significance. We utilized an experimentally tractable model to study the proliferative responses of rat fibroblasts when rendered hypoxic (0.5% oxygen) or anoxic (<0.01% oxygen). Hypoxic cells underwent G1 arrest, whereas anoxic cells also demonstrated S-phase arrest due to suppression of DNA initiation. Upon reoxygenation, only those cells arrested in G1 were able to resume proliferation. The oncoprotein E1a induced p53-independent apoptosis in anoxic cells, which when suppressed by Bcl-2 permitted proliferation despite anoxia. E1a expression led to marked increases in the transcription factor E2F, and overexpression of E2F-1 allowed proliferation in hypoxic cells, although it had minimal effect on the anoxic suppression of DNA initiation. We thus demonstrate two distinct cell cycle responses to low oxygen and suggest that alterations that lead to increased E2F can overcome hypoxic G1 arrest but that additional alterations, promoted by E1a expression, are necessary for neoplastic cells to proliferate despite anoxia.
Authors:
Lawrence B Gardner; Feng Li; Xuejie Yang; Chi V Dang
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Molecular and cellular biology     Volume:  23     ISSN:  0270-7306     ISO Abbreviation:  Mol. Cell. Biol.     Publication Date:  2003 Dec 
Date Detail:
Created Date:  2003-12-03     Completed Date:  2004-01-16     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  8109087     Medline TA:  Mol Cell Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9032-45     Citation Subset:  IM    
Affiliation:
Division of Hematology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. lawrence.gardner@med.nyu.edu
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MeSH Terms
Descriptor/Qualifier:
Adenovirus E1A Proteins / metabolism*
Animals
Cell Cycle
Cell Division
Cell Hypoxia / physiology*
Cell Line
DNA Replication / physiology*
Fibroblasts / cytology,  metabolism
G1 Phase
Models, Biological
Proto-Oncogene Proteins c-bcl-2 / metabolism
Rats
S Phase
Tumor Suppressor Protein p53 / metabolism
Grant Support
ID/Acronym/Agency:
K08 CA 89265/CA/NCI NIH HHS; N01 HV 28180/HV/NHLBI NIH HHS; R37 CA 51497/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Adenovirus E1A Proteins; 0/Proto-Oncogene Proteins c-bcl-2; 0/Tumor Suppressor Protein p53
Comments/Corrections

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