Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses.

Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses. Research Abstract Details 

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Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses. Abstract Text:

Current published data suggest that DNA mismatch repair (MMR) triggers prolonged G(2) cell cycle checkpoint arrest after alkylation damage from N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) by activating ATR (ataxia telangiectasia-Rad3-related kinase). However, analyses of isogenic MMR-proficient and MMR-deficient human RKO colon cancer cells revealed that although ATR/Chk1 signaling controlled G(2) arrest in MMR-deficient cells, ATR/Chk1 activation was not involved in MMR-dependent G(2) arrest. Instead, we discovered that disrupting c-Abl activity using STI571 (Gleevectrade mark, a c-Abl inhibitor) or stable c-Abl knockdown abolished MMR-dependent p73alpha stabilization, induction of GADD45alpha protein expression, and G(2) arrest. In addition, inhibition of c-Abl also increased the survival of MNNG-exposed MMR-proficient cells to a level comparable with MMR-deficient cells. Furthermore, knocking down GADD45alpha (but not p73alpha) protein levels affected MMR-dependent G(2) arrest responses. Thus, MMR-dependent G(2) arrest responses triggered by MNNG are dependent on a human MLH1/c-Abl/GADD45alpha signaling pathway and activity. Furthermore, our data suggest that caution should be taken with therapies targeting c-Abl kinase because increased survival of mutator phenotypes may be an unwanted consequence.

Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses. Publishing Authors By Initials

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Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses. Journal Published:

PUBLICATION TYPE: Journal Article

Journal: The Journal of biological chemistry

VOLUME: 283

Page Numbers: 21382-93

Journal Abbreviation: J. Biol. Chem.

ISSN: 0021-9258

DAY: 14

MONTH: 05

YEAR: 2008

Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses. Information

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LANGUAGE: eng

NlmUniqueID: 2985121

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Grant and Affiliation Information for Role of c-Abl Kinase in DNA Mismatch Repair-dependent G2 Cell Cycle Checkpoint Arrest Responses.

AFFILIATION: Laboratory of Molecular Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Comprehensive Cancer Center.

Country: United States

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MEDLINETA: J Biol Chem

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