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

doi:10.1016/j.molcel.2008.03.018

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 journal › Article › peer-review

127 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 language	English
Pages (from-to)	447-459
Number of pages	13
Journal	Molecular Cell
Volume	30
Issue number	4
DOIs	https://doi.org/10.1016/j.molcel.2008.03.018
State	Published - 23 May 2008
Externally published	Yes

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.

Funding

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.

Funders	Funder number
Flight Attendant Medical Research Institute
Weizmann Institute of Science
Israel Science Foundation

Keywords

CELLCYCLE
RNA

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10.1016/j.molcel.2008.03.018

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

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.",

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AU - Sivan, Gilad

AU - Reem, Eran

AU - Elroy-Stein, Orna

AU - Kimchi, Adi

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N2 - 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.

AB - 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.

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

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