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J. Biol. Chem., Vol. 280, Issue 39, 33280-33288, September 30, 2005

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Increased Expression of Mcl-1 Is Required for Protection against Serum Starvation in Phosphatase and Tensin Homologue on Chromosome 10 Null Mouse Embryonic Fibroblasts, but Repression of Bim Is Favored in Human Glioblastomas^*

From the Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Cambridge CB2 4AT, England

Inactivating mutations in the tumor suppressor gene phosphatase and tensin homologue on chromosome 10 (PTEN) result in elevated levels of phosphatidylinositol (3,4,5)-trisphosphate, activation of protein kinase B (PKB), and protection against apoptotic insults such as withdrawal of survival factors. Protection may arise through the inhibition of the pro-apoptotic protein Bim, which is normally repressed by a PKB-dependent mechanism. Here we show that PTEN^-/- immortalized mouse embryonic fibroblasts (MEFs) exhibit elevated PKB phosphorylation and are resistant to serum withdrawal-induced death, but exhibit normal Bim expression following withdrawal of serum. In contrast, expression of Mcl-1, a prosurvival member of the Bcl-2 family, was elevated in PTEN^-/- MEFs. Transient or stable overexpression of Mcl-1 in PTEN^+/- MEFs conferred resistance to serum withdrawal, whereas ablating expression of Mcl-1 in PTEN^-/- MEFs, using RNA interference, abolished their resistance to serum withdrawal-induced apoptosis. To determine if Mcl-1 is selected for overexpression in human tumors we examined human glioblastoma cell lines but found that loss of PTEN had no effect on Mcl-1 expression. In contrast, two of three PTEN^-/- glioblastoma cell lines exhibited low expression of Bim, which was refractory to serum withdrawal. These results indicate that the resistance of PTEN^-/- MEFs to serum withdrawal is largely due to the up-regulation of Mcl-1 but that loss of PTEN in tumor cell lines is more complex and may favor de-regulation of different apoptotic regulators such as Bim.

Received for publication, July 27, 2005

^* This work was supported in part by a grant from Cancer Research UK (Grant SP2458/0201) and a Competitive Strategic Grant from the Biotechnology and Biological Sciences Research Council to the Babraham Institute. 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 To whom correspondence may be addressed. Tel.: 44-1223-496-479; Fax: 44-1223-496-043; E-mail: mark.austin{at}bbsrc.ac.uk. ² To whom correspondence may be addressed. Tel.: 44-1223-496-453; Fax: 44-1223-496-043; E-mail: simon.cook{at}bbsrc.ac.uk.

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