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J. Biol. Chem., Vol. 283, Issue 4, 2223-2230, January 25, 2008

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UV-mediated Regulation of the Anti-senescence Factor Tbx2^*

Amaal Abrahams¹, Shaheen Mowla, M. Iqbal Parker, Colin R. Goding^¶, and Sharon Prince, Supported by the National Research Foundation and University of Cape Town and the South African Medical Research Council²

From the Divisions of Medical Biochemistry and Cell Biology, Faculty of Health Sciences, University of Cape Town, Observatory 7925, Cape Town, South Africa and ^¶Signaling and Development Laboratory, Marie Curie Research Institute, The Chart, Oxted, Surrey RH8 OTL, United Kingdom

Several lines of evidence have implicated members of the developmentally important T-box gene family in cell cycle regulation and in cancer. Importantly, the highly related T-box factors Tbx2 and Tbx3 can suppress senescence through repressing the cyclin-dependent kinase inhibitors p19^ARF and p21^{WAF1/CIP1/SDII}. Furthermore, Tbx2 is up-regulated in several cancers, including melanomas where it was shown to function as an anti-senescence factor, suggesting that this may be one of the mechanisms by which T-box proteins contribute to the oncogenic process. However, very little is known about whether Tbx2 is regulated by p21-mediated stress-induced senescence signaling pathways. In this study, using the MCF-7 breast cancer cell line known to overexpress Tbx2, we show that in response to stress induced by ultraviolet irradiation the Tbx2 protein is specifically phosphorylated by the p38 mitogen-activated protein kinase. Using site-directed mutagenesis and in vitro kinase assays, we have identified serine residues 336, 623, and 675 in the Tbx2 protein as the p38 target sites and show that these sites are phosphorylated in vivo. Importantly, we show by Western blotting, immunofluorescence, and reporter assays that this phosphorylation leads to increased Tbx2 protein levels, predominant nuclear localization of the protein, and an increase in the ability of Tbx2 to repress the p21^{WAF1/CIP1/SDII} promoter. These results show for the first time that the ability of Tbx2 to repress the p21 gene is enhanced in response to a stress-induced senescence pathway, which leads to a better understanding of the regulation of the anti-senescence function of Tbx2.

Received for publication, July 10, 2007 , and in revised form, November 15, 2007.

^* This work was supported by grants from the Wellcome Trust (to S. P. and C. R. 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.

¹ Supported by the National Research Foundation and University of Cape Town, the German Academic Exchange Service, and a Harry Crossley Foundation research fellowship.

² To whom correspondence should be addressed. Tel.: 27-21-406-6240; Fax: 27-21-448-7226; E-mail: sharon.prince{at}uct.ac.za.

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