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J. Biol. Chem., Vol. 279, Issue 25, 26115-26125, June 18, 2004

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p53 Induces NF-B Activation by an IB Kinase-independent Mechanism Involving Phosphorylation of p65 by Ribosomal S6 Kinase 1^*

Jan Bohuslav, Lin-feng Chen, Hakju Kwon, Yajun Mu, and Warner C. Greene¶

From the Gladstone Institute of Virology and Immunology and the Departments of Medicine and of Microbiology and Immunology, University of California, San Francisco, California 94143-1234

Apoptosis induced by p53 has been proposed to involve activation of the transcription factor NF-B. Here we describe the novel molecular mechanism through which p53 and DNA-damaging agents activate NF-B. NF-B induction by p53 does not occur through classical activation of the IB kinases and degradation of IB. Rather, p53 expression stimulates the serine/threonine kinase ribosomal S6 kinase 1 (RSK1), which in turn phosphorylates the p65 subunit of NF-B. The lower affinity of RSK1-phosphorylated p65 for its negative regulator, IB, decreases IB-mediated nuclear export of shuttling forms of NF-B, thereby promoting the binding and action of NF-B on cognate B enhancers. These findings highlight a rather unusual pathway of NF-B activation, which is utilized by the p53 tumor suppressor.

Received for publication, December 10, 2003 , and in revised form, April 1, 2004.

^* This work was supported by National Institutes of Health Grant RO1CA089001 (to W. C. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Gladstone Institute of Virology and Immunology, P.O. Box 419100, San Francisco, CA 94141-9100. Tel.: 415-826-7500; Fax: 415-826-1817; E-mail: wgreene{at}gladstone.ucsf.edu.

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