Research article summary (published 15 Sep 2009):

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

Full Abstract

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.

Author information

Author/s: Sun, Guoming (G); Jin, Shunqian (S); Baskaran, R (R);

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

Grants: GM60945 (Agency:NIGMS NIH HHS)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural

Journal: Experimental cell research (Exp Cell Res), published in United States. (Language: eng)

Reference: 2009-Nov; vol 315 (issue 18) : pp 3163-75

Dates: Created 2009/10/19; Completed 2009/11/06; Revised 2009/11/06;

PMID: 19766113, status: MEDLINE (last retrieved date: 11/9/2009)

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

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MeSH headings (categories)

This article was linked to the MeSH Headings (categories) shown below.

Adaptor Proteins, Signal Transducing - drug effects; metabolism Alkylating Agents - toxicity Antineoplastic Agents - pharmacology Apoptosis Carcinogens - toxicity DNA Mismatch Repair DNA-Binding Proteins - antagonists & inhibitors; metabolism Hela Cells Homeodomain Proteins - agonists; metabolism Humans Methylnitronitrosoguanidine - toxicity

Nuclear Proteins - antagonists & inhibitors; drug effects; metabolism Oligonucleotides - metabolism Piperazines - pharmacology Proto-Oncogene Proteins c-abl - drug effects; metabolism Pyrimidines - pharmacology RNA, Small Interfering - metabolism Receptors, Cytoplasmic and Nuclear - agonists; metabolism Signal Transduction - drug effects; physiology Transfection Tumor Suppressor Protein p53 - drug effects; metabolism Tumor Suppressor Proteins - agonists; antagonists & inhibitors; metabolism

Note: Bold headings indicate primary MeSH headings or qualifiers.

Associated Chemicals: Adaptor Proteins, Signal Transducing (0) ; Alkylating Agents (0) ; Antineoplastic Agents (0) ; Carcinogens (0) ; DNA-Binding Proteins (0) ; Homeodomain Proteins (0) ; ING2 protein, human (0) ; MLH1 protein, human (0) ; Nuclear Proteins (0) ; Oligonucleotides (0) ; Piperazines (0) ; Pyrimidines (0) ; RNA, Small Interfering (0) ; Receptors, Cytoplasmic and Nuclear (0) ; Tumor Suppressor Protein p53 (0) ; Tumor Suppressor Proteins (0) ; tumor suppressor protein p73 (0) ; imatinib (152459-95-5) ; Methylnitronitrosoguanidine (70-25-7) ; Proto-Oncogene Proteins c-abl (EC 2.7.1.112)

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