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J. Biol. Chem., Vol. 280, Issue 16, 16019-16029, April 22, 2005

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Tumor Suppressor SMAR1 Activates and Stabilizes p53 through Its Arginine-Serine-rich Motif^*

Archana Jalota, Kamini Singh¶, Lakshminarasimhan Pavithra, Ruchika Kaul-Ghanekar, Shahid Jameel||**, and Samit Chattopadhyay

From the National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 411007 and ^|| International Center for Genetic Engineering and Biotechnology, Aruna Asaf Ali Marg, New Delhi 110067, India

Various stresses and DNA-damaging agents trigger transcriptional activity of p53 by post-translational modifications, making it a global regulatory switch that controls cell proliferation and apoptosis. Earlier we have shown that the novel MAR-associated protein SMAR1 interacts with p53. Here we delineate the minimal domain of SMAR1 (the arginine-serine-rich domain) that is phosphorylated by protein kinase C family proteins and is responsible for p53 interaction, activation, and stabilization within the nucleus. SMAR1-mediated stabilization of p53 is brought about by inhibiting Mdm2-mediated degradation of p53. We also demonstrate that this arginine-serine (RS)-rich domain triggers the various cell cycle modulating proteins that decide cell fate. Furthermore, phenotypic knock-down experiments using small interfering RNA showed that SMAR1 is required for activation and nuclear retention of p53. The level of phosphorylated p53 was significantly increased in the thymus of SMAR1 transgenic mice, showing in vivo significance of SMAR1 expression. This is the first report that demonstrates the mechanism of action of the MAR-binding protein SMAR1 in modulating the activity of p53, often referred to as the "guardian of the genome."

Received for publication, November 23, 2004 , and in revised form, January 14, 2005.

^* The work was supported by grants from Department of Biotechnology and Department of Science and Technology, New Delhi, India. 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.

Research fellow of University Grants Commission, Government of India.

^¶ Research fellow of Indian Council of Medical Research, Government of India.

^** International Senior Research Fellow of the Wellcome Trust.

To whom correspondence should be addressed: National Center for Cell Science, Pune University Campus, Ganeshkhind, Pune 11007, India. Tel.: 91-20-2569-0922; Fax: 91-20-2569-2259; E-mail: samit{at}nccs.res.in.

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