Negative regulation of p53 expression is an essential, rate-limiting function of Jun in the control of cell cycle progression

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The tumor suppressor gene p53 is inactivated by mutations in >50% of human tumors, including breast cancers. Here we show that p53 expression is negatively regulated by the Jun proto-oncogene, which encodes a component of the mitogen-inducible immediate-early transcription factor AP-1 and has been implicated as a positive regulator of cell proliferation. In fibroblasts derived from Jun-/- mouse fetuses, the tumor suppressor gene p53 and its target gene, the CDK inhibitor p21, are expressed at elevated levels, whereas overexpression of Jun represses p53 and p21 expression. Surprisingly, protein stabilisation, the common mechanism of p53 regulation, does not seem to be involved in upregulation of p53 in Jun-/- fibroblasts. Rather, Jun was found to negatively regulate transcription of p53 by direct binding to a conserved AP-1 site in the p53 promoter. Furthermore, overexpression of Jun accelerates cell proliferation, whereas the absence of Jun results in a severe proliferation defect and a prolonged crisis prior to spontaneous immortalisation. The cyclin D1- and cyclin E-dependent kinases (CDKs) and transcription factor E2F are poorly activated, resulting in inefficient G1 to S-phase progression. Importantly, deletion of p53 abrogates all defects of Jun-/- cells in cell cycle progression, proliferation, immortalisation, and activation of G1 CDKs and E2F. These results demonstrate that the sole rate-limiting function of Jun in fibroblast proliferation is negative regulation of p53 expression, and establish a mechanistic link between Jun-dependent mitogenic signalling and cell cycle regulation.