Control of cell cycle progression by c-Jun is p53 dependent

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 pr...

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Bibliographic Details
Published in:Genes & development 1999-03, Vol.13 (5), p.607-619
Main Authors: Schreiber, M, Kolbus, A, Piu, F, Szabowski, A, Möhle-Steinlein, U, Tian, J, Karin, M, Angel, P, Wagner, E F
Format: Article
Language:English
Subjects:
3T3 Cells
Animals
Cell Cycle - physiology
Cell Division
Cyclin G
Cyclin G1
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases - metabolism
Cyclins - biosynthesis
Cyclins - metabolism
Enzyme Activation
Mice
Promoter Regions, Genetic
Proto-Oncogene Proteins c-jun - metabolism
Research Paper
Tumor Suppressor Protein p53 - biosynthesis
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Summary: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.
ISSN:0890-9369
DOI:10.1101/gad.13.5.607