Role of c-Abl kinase in DNA mismatch repair-dependent G2 cell cycle checkpoint arrest responses.
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 (Gleevec, 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.
Wagner
Mark W
MW
Laboratory of Molecular Stress Responses, Program in Cell Stress and Cancer Nanomedicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Li
Long Shan
LS
Morales
Julio C
JC
Galindo
Cristi L
CL
Garner
Harold R
HR
Bornmann
William G
WG
Boothman
David A
DA
D000970:Antineoplastic Agents / Q000494:pharmacology; D020137:Base Pair Mismatch; D001549:Benzamides; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004260:DNA Repair; D004305:Dose-Response Relationship, Drug; D016195:G2 Phase; D006801:Humans; D000068877:Imatinib Mesylate; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D008954:Models, Biological; D009687:Nuclear Proteins / Q000378:metabolism; D010879:Piperazines; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D000097642:GADD45 Proteins
D000970:Antineoplastic Agents; D001549:Benzamides; D018797:Cell Cycle Proteins; D000068877:Imatinib Mesylate; D008769:Methylnitronitrosoguanidine; D009687:Nuclear Proteins; D010879:Piperazines; D016315:Proto-Oncogene Proteins c-abl; D011743:Pyrimidines; C439070:GADD45A protein, human; D000097642:GADD45 Proteins