Control of cell cycle progression by c-Jun is p53 dependent (original) (raw)
- Martin Schreiber,
- Andrea Kolbus,
- Fabrice Piu,
- Axel Szabowski,
- Uta Möhle-Steinlein,
- Jianmin Tian,
- Michael Karin,
- Peter Angel, and
- Erwin F. Wagner
- Research Institute of Molecular Pathology (IMP), A-1030 Vienna, Austria; Deutsches Krebsforschungszentrum (DKFZ), Division of Signal Transduction and Growth Control, D-69120 Heidelberg, Germany; Department of Pharmacology, University of California at San Diego, La Jolla, California 92093-0636 USA
Abstract
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.
Footnotes
Present addresses: 4Vienna Biocenter, Department of Microbiology and Genetics, A-1030 Vienna, Austria; 5Acadia Pharmaceuticals, Inc., San Diego, California 92121 USA.
↵Corresponding author.
E-MAIL wagner{at}ht.imp.univie.ac.at; FAX 43-1798 71 53.
- Received July 16, 1998.
- Accepted December 23, 1998.
Cold Spring Harbor Laboratory Press