Mcl-1 ubiquitination and destruction

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

Research output: Contribution to journalArticlepeer-review

68 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)239-244
Number of pages6
JournalOncotarget
Volume2
Issue number3
DOIs
Publication statusPublished - 2011

Keywords

  • Apoptosis
  • Cell cycle
  • Fbw7
  • GSK3
  • Mcl-1
  • Phosphorylation
  • SCF
  • Tumor suppressor
  • Ubiquitination

ASJC Scopus subject areas

  • Oncology

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