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Mcl-1 ubiquitination and destruction Inuzuka H; Fukushima H; Shaik S; Liu P; Lau AW; Wei WOncotarget 2011[Mar]; 2 (3): 239-44Loss 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.|Cell Cycle Proteins/genetics/*metabolism[MESH]|Cell Line, Tumor[MESH]|F-Box Proteins/genetics/*metabolism[MESH]|F-Box-WD Repeat-Containing Protein 7[MESH]|Humans[MESH]|Myeloid Cell Leukemia Sequence 1 Protein[MESH]|Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy/genetics/*metabolism[MESH]|Proto-Oncogene Proteins c-bcl-2/antagonists & inhibitors/*metabolism[MESH]|Ubiquitin-Protein Ligases/deficiency/genetics/*metabolism[MESH]|Ubiquitination[MESH] |
