Document Detail


Control of cell cycle progression by c-Jun is p53 dependent.
MedLine Citation:
PMID:  10072388     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The c-jun proto-oncogene encodes a component of the mitogen-inducible immediate-early transcription factor AP-1 and has been implicated as a positive regulator of cell proliferation and G1-to-S-phase progression. Here we report that fibroblasts derived from c-jun-/- mouse fetuses exhibit a severe proliferation defect and undergo a prolonged crisis before spontaneous immortalization. The cyclin D1- and cyclin E-dependent kinases (CDKs) and transcription factor E2F are poorly activated, resulting in inefficient G1-to-S-phase progression. Furthermore, the absence of c-Jun results in elevated expression of the tumor suppressor gene p53 and its target gene, the CDK inhibitor p21, whereas overexpression of c-Jun represses p53 and p21 expression and accelerates cell proliferation. Surprisingly, protein stabilization, the common mechanism of p53 regulation, is not involved in up-regulation of p53 in c-jun-/- fibroblasts. Rather, c-Jun regulates transcription of p53 negatively by direct binding to a variant AP-1 site in the p53 promoter. Importantly, deletion of p53 abrogates all defects of cells lacking c-Jun in cell cycle progression, proliferation, immortalization, and activation of G1 CDKs and E2F. These results demonstrate that an essential, rate-limiting function of c-Jun in fibroblast proliferation is negative regulation of p53 expression, and establish a mechanistic link between c-Jun-dependent mitogenic signaling and cell-cycle regulation.
Authors:
M Schreiber; A Kolbus; F Piu; A Szabowski; U Möhle-Steinlein; J Tian; M Karin; P Angel; E F Wagner
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Genes & development     Volume:  13     ISSN:  0890-9369     ISO Abbreviation:  Genes Dev.     Publication Date:  1999 Mar 
Date Detail:
Created Date:  1999-04-27     Completed Date:  1999-04-27     Revised Date:  2013-04-18    
Medline Journal Info:
Nlm Unique ID:  8711660     Medline TA:  Genes Dev     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  607-19     Citation Subset:  IM    
Affiliation:
Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria.
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MeSH Terms
Descriptor/Qualifier:
3T3 Cells
Animals
Cell Cycle / physiology*
Cell Division
Cyclin G
Cyclin G1
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases / metabolism
Cyclins / biosynthesis,  metabolism
Enzyme Activation
Mice
Promoter Regions, Genetic
Proto-Oncogene Proteins c-jun / metabolism*
Tumor Suppressor Protein p53 / biosynthesis*
Grant Support
ID/Acronym/Agency:
ES 04151/ES/NIEHS NIH HHS; ES 06376/ES/NIEHS NIH HHS
Chemical
Reg. No./Substance:
0/Ccng1 protein, mouse; 0/Cdkn1a protein, mouse; 0/Cyclin G; 0/Cyclin G1; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Proto-Oncogene Proteins c-jun; 0/Tumor Suppressor Protein p53; EC 2.7.11.22/Cyclin-Dependent Kinases
Comments/Corrections

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


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