Document Detail


Downregulation of PCNA potentiates p21-mediated growth inhibition in response to hyperoxia.
MedLine Citation:
PMID:  17085526     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Prolonged exposure to hyperoxia inhibits cell proliferation in G1 via increased expression of p21. While p21 inhibits proliferating cell nuclear antigen (PCNA)-dependent DNA synthesis, it can also directly lower PCNA abundance; however, it is unclear whether loss of PCNA contributes to growth arrest. Here, we investigate how PCNA loss affects ability of p21 to exert G1 growth arrest of lung epithelial cells exposed to hyperoxia. In A549 cells that express p21 and growth arrest in G1 during hyperoxia, small interfering RNA (siRNA) knockdown of p21 led to G1 checkpoint bypass, increased cell death, and restoration of PCNA expression. Conditional overexpression of the PCNA binding domain of p21 in H1299 cells that do not normally express p21, or exposure to hyperoxia, caused a time-dependent loss of PCNA. Titrating PCNA levels using siRNA to approximate the low amount observed in cells expressing p21 resulted in S phase arrest. While lowering PCNA by itself caused S phase arrest, the combination of hyperoxia and siRNA against PCNA dramatically reduced PCNA abundance resulting in G1 arrest. G1 growth arrest was markedly enhanced upon the addition of p21 to these cells. Our findings suggest a model in which reducing expression of the abundant protein PCNA allows the less abundant protein p21 to be more effective at suppressing the processivity functions of remaining PCNA, thereby fully exerting the G1 checkpoint. Given that high p21 expression is often associated with lower PCNA abundance, our findings are suggestive of a global growth inhibitory mechanism involving p21-mediated PCNA suppression.
Authors:
Sean C Gehen; Peter F Vitiello; Robert A Bambara; Peter C Keng; Michael A O'Reilly
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2006-11-03
Journal Detail:
Title:  American journal of physiology. Lung cellular and molecular physiology     Volume:  292     ISSN:  1040-0605     ISO Abbreviation:  Am. J. Physiol. Lung Cell Mol. Physiol.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-07     Completed Date:  2007-04-10     Revised Date:  2007-12-03    
Medline Journal Info:
Nlm Unique ID:  100901229     Medline TA:  Am J Physiol Lung Cell Mol Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  L716-24     Citation Subset:  IM    
Affiliation:
Department of Environmental Medicine, University of Rochester, 601 Elmwood Ave., Rochester, NY 14642, USA.
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma / metabolism,  pathology
Animals
Cell Proliferation
Cyclin-Dependent Kinase Inhibitor p21 / genetics,  physiology*
Down-Regulation
G1 Phase
Humans
Hyperoxia / metabolism*
Lung Neoplasms / metabolism,  pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Proliferating Cell Nuclear Antigen / chemistry,  genetics,  metabolism*
RNA, Small Interfering / pharmacology
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
ES-01247/ES/NIEHS NIH HHS; ES-07026/ES/NIEHS NIH HHS; GM-024441/GM/NIGMS NIH HHS; HL-67392/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p21; 0/Proliferating Cell Nuclear Antigen; 0/RNA, Small Interfering

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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