Send to

Choose Destination
See comment in PubMed Commons below
Exp Cell Res. 2009 Nov 1;315(18):3163-75. doi: 10.1016/j.yexcr.2009.09.010. Epub 2009 Sep 17.

MMR/c-Abl-dependent activation of ING2/p73alpha signaling regulates the cell death response to N-methyl-N'-nitro-N-nitrosoguanidine.

Author information

Department of Microbiology and Molecular Genetics, School of Medicine, University of Pittsburgh, E1205 Biomedical Science Tower, Pittsburgh, PA 15261, USA.


Agents inducing O(6)-methylguanine (O(6)MeG) in DNA such as N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) are cytotoxic and a deficiency in mismatch repair (MMR) results in lack of sensitivity to this genotoxin (termed alkylation tolerance). Here, we show that ING2, a member of the inhibitor of growth family, is required for cell death induced by MNNG. We further observe that MNNG treatment increases cellular protein levels of ING2 that is dependent on intact MMR function and that MNNG-induced ING2 localizes and associates with p73alpha in the nucleus. Suppression of ING2 by short hairpin RNA (shRNA) in MMR-proficient colorectal cancer cells decreased its sensitivity to MNNG and, in addition, abrogated MNNG-induced stabilization and acetylation of p73alpha. Interestingly, suppression of p73alpha had a greater impact on MNNG-induced cell death than ING2 leading us to conclude that ING2 regulates the cell death response, in part, through p73alpha. Inhibition of c-Abl by STI571 or suppression of c-Abl expression by shRNA blocked ING2 induction and p73alpha acetylation induced by this alkylator. Similarly, suppression of MMR (MLH1) by shRNA abrogated ING2 induction/p73alpha acetylation. Taken together, these results demonstrate that MLH1/c-Abl-dependent activation of ING2>p73alpha signaling regulates cell death triggered by MNNG and further suggests that dysregulation of this event may, in part, be responsible for alkylation tolerance observed in MMR compromised cells.

[Indexed for MEDLINE]
Free PMC Article

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms


Grant support

PubMed Commons home

PubMed Commons

How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center