SCFFBW7 regulates cellular apoptosis by targeting MCL1 for ubiquitylation and destruction. (Nature. 2011 Mar 3, 471(7336):104-9)

報告日期: 2012/11/09
報告時間: 16:00/16:50
報告學生: 吳菁山
講評老師: 黃溫雅
附件下載: 下載[1242-1350385911-1.pdf] 

 

SCFFBW7 regulates cellular apoptosis by targeting

MCL1 for ubiquitylation and destruction

Hiroyuki Inuzuka1, Shavali Shaik, Ichiro Onoyama, Daming Gao1, Alan Tseng, Richard S. Maser, Bo Zhai, Lixin Wan, Alejandro Gutierrez, Alan W. Lau, Yonghong Xiao, Amanda L. Christie, Jon Aster, Jeffrey Settleman, Steven P. Gygi5, Andrew L. Kung, Thomas Look, Keiichi I. Nakayama, Ronald A. DePinho & Wenyi Wei

Nature.471 104-109, (2011).

Speaker: Jing-Shan Wu (吳菁山)                                 Time: 16:00-16:50

Commentator:Wenya Huang (黃溫雅) Ph.D            Place: Room 602

 

Abstract                                                                                                    

T-cell acute lymphoblastic leukemia (T-ALL) is a neoplastic disease of lymphoblasts committed to the T-cell lineage. While this type of cancer only accounts for a subset of acutelymphoblastic leukemias, it is often characterized as an aggressive disease that inevitablyleads to poor clinical outcomes. Mutations in the FBW7 gene are commonly found in T-ALL. The gene FBW7 is a tumour suppressor, whichcan protect cells from carcinogenic changes. It is known that FBW7is inactivated in several tumour types, particularly in T-cell acute lymphoblastic leukaemia (T-ALL) and in breast and colon cancers. The precise molecular mechanisms how FBW7 exerts  antitumour activity is an area of intensive investigation. The mechanism of FBW7-mediated destruction of key proteins relevant to cancers,including Jun6, Myc7, cyclin E8 and notch 1, in which all of these oncoproteins are activated and overexpressed in various human cancers, including leukaemia. The E3 ubiquitin ligase SCFFBW7 (a SKP1–cullin-1–F-box complex that contains FBW7 as the F-box protein) regulates cellular apoptosis by targeting MCL1, a pro-survival BCL2 family member, for ubiquitination and degradation in a GSK3-dependent manner. A close relationship between FBW7 loss and MCL1 overexpression is also showed in Human T-ALL cell lines. FBW7 reconstitution or MCL1 depletion restores sensitivity to ABT-737. This study established MCL1 as a therapeutically target as a personalized treatment in cancers where Fbw7 function is lost.

 

Reference:

Alan W. Lau, Hidefumi Fukushima, and Wenyi Wei, The Fbw7 and Beta-TRCP E3 ubiquitin ligases and their roles in tumorigenesis. Front Biosci. 2012 Jun 1;17:2197-212