Mcl-1 Ubiquitination and Destruction

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Mcl-1 Ubiquitination and Destruction

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Title: Mcl-1 Ubiquitination and Destruction
Author: Fukushima, Hidefumi; Lau, Alan W.; Inuzuka, Hiroyuki; Shaik, Shavali; Liu, Pengda; Wei, Wenyi

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Citation: Inuzuka, Hiroyuki, Hidefumi Fukushima, Shavali Shaik, Pengda Liu, Alan W. Lau, and Wenyi Wei. 2011. Mcl-1 ubiquitination and destruction. Oncotarget 2(3): 239-244.
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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 SCF\(^{Fbw7}\) 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.
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3260810/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10288518
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