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| Subject Categories: Signal Transduction |
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| The EMBO Journal
(2006) 25, 3774–3783, doi:10.1038/sj.emboj.7601263 Published online 3 August 2006 |
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| MUC1 oncoprotein blocks nuclear targeting of c-Abl in the apoptotic response to DNA damage |
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| Deepak Raina1, Rehan Ahmad1, Shailendra Kumar2, Jian Ren, Kiyotsugu Yoshida3, Surender Kharbanda and Donald Kufe |
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Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA To whom correspondence should be addressed Donald Kufe, Dana-Farber Cancer Institute, Harvard Medical School, Binny Street, Boston, MA 02115, USA. Tel.: +1 617 632 3141 Fax: +1 617 632 2934; E-mail: donald_kufe@dfci.harvard.edu 1 These authors contributed equally to this work 2 Present address: Matritech Inc., Newton, MA 02460, USA 3 Present address: Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan Received 15 December 2005; Accepted 7 July 2006; Published online 3 August 2006. |
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| Abstract |
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| The nonreceptor c-Abl tyrosine kinase binds to cytosolic 14-3-3 proteins and is targeted to the nucleus in the apoptotic response to DNA damage. The MUC1 oncoprotein is overexpressed by most human carcinomas and blocks the induction of apoptosis by genotoxic agents. Using human carcinoma cells with gain and loss of MUC1 function, we show that nuclear targeting of c-Abl by DNA damage is abrogated by a MUC1-dependent mechanism. The results demonstrate that c-Abl phosphorylates MUC1 on Tyr-60 and forms a complex with MUC1 by binding of the c-Abl SH2 domain to the pTyr-60 site. Binding of MUC1 to c-Abl attenuates phosphorylation of c-Abl on Thr-735 and the interaction between c-Abl and cytosolic 14-3-3. We also show that expression of MUC1 with a mutation at Tyr-60 (i) disrupts the interaction between MUC1 and c-Abl, (ii) relieves the MUC1-induced block of c-Abl phosphorylation on Thr-735 and binding to 14-3-3, and (iii) attenuates the MUC1 antiapoptotic function. These findings indicate that MUC1 sequesters c-Abl in the cytoplasm and thereby inhibits apoptosis in the response to genotoxic anticancer agents. |
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| Keywords: apoptosis, c-Abl, DNA damage, MUC1, 14-3-3 |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated NEWS AND VIEWSStress and death: breaking up the c-Abl/14-3-3 complex in apoptosis Nature Cell Biology News and Views (01 Mar 2005) Nature News and Views (24 Jun 1999) RESEARCHJournal of Cerebral Blood Flow & Metabolism Original Article Nature Cell Biology Letter (01 Mar 2005) |
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