ATM-dependent expression of IEX-1 controls nuclear accumulation of Mcl-1 and the DNA damage response

作者：Pawlikowska P; Leray I; de Laval B; Guihard S; Kumar R; Rosselli F; Porteu F^*

来源：Cell Death and Differentiation, 2010, 17(11): 1739-1750.

DOI：10.1038/cdd.2010.56

• IEX-1
• Mcl-1
• DNA damage
• checkpoint
• apoptosis

The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by c-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy. Cell Death and Differentiation (2010) 17, 1739-1750; doi: 10.1038/cdd.2010.56; published online 14 May 2010

• 出版日期2010-11