TY - JOUR
T1 - Role of c-Abl kinase in DNA mismatch repair-dependent G2 cell cycle checkpoint arrest responses
AU - Wagner, Mark W.
AU - Long, Shan Li
AU - Morales, Julio C.
AU - Galindo, Cristi L.
AU - Garner, Harold R.
AU - Bornmann, William G.
AU - Boothman, David A.
PY - 2008/8/1
Y1 - 2008/8/1
N2 - Current published data suggest that DNA mismatch repair (MMR) triggers prolonged G2 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 G2 arrest in MMR-deficient cells, ATR/Chk1 activation was not involved in MMR-dependent G2 arrest. Instead, we discovered that disrupting c-Abl activity using STI571 (Gleevec™, a c-Abl inhibitor) or stable c-Abl knockdown abolished MMR-dependent p73α stabilization, induction of GADD45α protein expression, and G2 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 GADD45α (but not p73α) protein levels affected MMR-dependent G2 arrest responses. Thus, MMR-dependent G2 arrest responses triggered by MNNG are dependent on a human MLH1/c-Abl/GADD45α 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.
AB - Current published data suggest that DNA mismatch repair (MMR) triggers prolonged G2 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 G2 arrest in MMR-deficient cells, ATR/Chk1 activation was not involved in MMR-dependent G2 arrest. Instead, we discovered that disrupting c-Abl activity using STI571 (Gleevec™, a c-Abl inhibitor) or stable c-Abl knockdown abolished MMR-dependent p73α stabilization, induction of GADD45α protein expression, and G2 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 GADD45α (but not p73α) protein levels affected MMR-dependent G2 arrest responses. Thus, MMR-dependent G2 arrest responses triggered by MNNG are dependent on a human MLH1/c-Abl/GADD45α 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.
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U2 - 10.1074/jbc.M709953200
DO - 10.1074/jbc.M709953200
M3 - Article
C2 - 18480061
AN - SCOPUS:52049122158
SN - 0021-9258
VL - 283
SP - 21382
EP - 21393
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 31
ER -