DAP5 Promotes Cap-Independent Translation of Bcl-2 and CDK1 to Facilitate Cell Survival during Mitosis

Lea Marash, Noa Liberman, Sivan Henis-Korenblit, Gilad Sivan, Eran Reem, Orna Elroy-Stein, Adi Kimchi

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

Abstract

DAP5 is an eIF4G protein previously implicated in mediating cap-independent translation in response to cellular stresses. Here we report that DAP5 is crucial for continuous cell survival in nonstressed cells. The knockdown of endogenous DAP5 induced M phase-specific caspase-dependent apoptosis. Bcl-2 and CDK1 were identified by two independent screens as DAP5 translation targets. Notably, the activity of the Bcl-2 IRES was reduced in DAP5 knockdown cells and a selective shift of Bcl-2 mRNA toward light polysomal fractions was detected. Furthermore, a functional IRES was identified in the 5′UTR of CDK1. At the cellular level, attenuated translation of CDK1 by DAP5 knockdown decreased the phosphorylation of its M phase substrates. Ectopic expression of Bcl-2 or CDK1 proteins partially reduced the extent of caspase activation caused by DAP5 knockdown. Thus, DAP5 is necessary for maintaining cell survival during mitosis by promoting cap-independent translation of at least two prosurvival proteins.

Original languageEnglish
Pages (from-to)447-459
Number of pages13
JournalMolecular Cell
Volume30
Issue number4
DOIs
StatePublished - 23 May 2008
Externally publishedYes

Bibliographical note

Funding Information:
We thank R. Lloyd for providing the bicistronic constructs with Bcl-2 IRES. We thank Dr. S. Bialik for critical reading of this manuscript, Dr. A. Gamliel for generating the DAP5 shRNA construct, E. Zalckvar for generating the HcRed shRNA construct, and A. Sharp for the assistance with FACS analysis. This work was supported by the Center of Excellence grant from the Flight Attendant Medical Research Institute (FAMRI) to A.K., the Kahn Fund for System Biology at the Weizmann Institute of Science to A.K., and by a grant from the Israel Science Foundation (to O.E.-S.). A.K. is the incumbent of Helena Rubinstein Chair of Cancer Research.

Keywords

  • CELLCYCLE
  • RNA

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