Oncotarget

Research Perspectives:

Mcl-1 Ubiquitination and Destruction

Hiroyuki Inuzuka, Hidefumi Fukushima, Shavali Shaik, Pengda Liu, Alan W. Lau and Wenyi Wei _

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Oncotarget. 2011; 2:239-244. https://doi.org/10.18632/oncotarget.242

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Abstract

Hiroyuki Inuzuka, Hidefumi Fukushima, Shavali Shaik, Pengda Liu, Alan W. Lau and Wenyi Wei

*Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215

Keywords: Ubiquitination, SCF, Fbw7, GSK3, Mcl-1, Apoptosis, Tumor Suppressor, Phosphorylation, Cell Cycle

Received: March 18, 2011; Accepted: March 18, 2011; Published: March 19, 2011;

Correspondence:

Wenyi Wei, e-mail:

Abstract

Loss of the Fbw7 tumor suppressor is common in diverse human cancer types, including T-Cell Acute Lymphoblastic Leukemia (T-ALL), although the mechanistic basis of its anti-oncogenic activity remains largely unclear. We recently reported that SCFFbw7 regulates cellular apoptosis by controlling the ubiquitination and destruction of the pro-survival protein, Mcl-1, in a GSK3 phosphorylation-dependent manner. We found that human T-ALL cell lines displayed a close relationship between Fbw7 loss and Mcl-1 overexpression. More interestingly, T-ALL cell lines that are deficient in Fbw7 are particularly sensitive to sorafenib, a multi-kinase inhibitor that has been demonstrated to reduce Mcl-1 expression through an unknown mechanism. On the other hand, Fbw7-deficient T-ALL cell lines are much more resistant to the Bcl-2 antagonist, ABT-737. Furthermore, reconstitution of Fbw7 or depletion of Mcl-1 in Fbw7-deficient cells restores ABT-737 sensitivity, suggesting that elevated Mcl-1 expression is important for Fbw7-deficient cells to evade apoptosis. Therefore, our work provides a novel molecular mechanism for the tumor suppression function of Fbw7. Furthermore, it provides the rationale for targeted usage of Mcl-1 antagonists to treat Fbw7-deficient T-ALL patients.


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