DNA Mismatch Repair-dependent Activation of c-Abl/p73 /GADD45 -mediated Apoptosis

Laboratory of Molecular Stress Responses, Department of Oncology, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 06/2008; 283(31):21394-403. DOI: 10.1074/jbc.M709954200
Source: PubMed


Cells with functional DNA mismatch repair (MMR) stimulate G(2) cell cycle checkpoint arrest and apoptosis in response to N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). MMR-deficient cells fail to detect MNNG-induced DNA damage, resulting in the survival of "mutator" cells. The retrograde (nucleus-to-cytoplasm) signaling that initiates MMR-dependent G(2) arrest and cell death remains undefined. Since MMR-dependent phosphorylation and stabilization of p53 were noted, we investigated its role(s) in G(2) arrest and apoptosis. Loss of p53 function by E6 expression, dominant-negative p53, or stable p53 knockdown failed to prevent MMR-dependent G(2) arrest, apoptosis, or lethality. MMR-dependent c-Abl-mediated p73alpha and GADD45alpha protein up-regulation after MNNG exposure prompted us to examine c-Abl/p73alpha/GADD45alpha signaling in cell death responses. STI571 (Gleevec, a c-Abl tyrosine kinase inhibitor) and stable c-Abl, p73alpha, and GADD45alpha knockdown prevented MMR-dependent apoptosis. Interestingly, stable p73alpha knockdown blocked MMR-dependent apoptosis, but not G(2) arrest, thereby uncoupling G(2) arrest from lethality. Thus, MMR-dependent intrinsic apoptosis is p53-independent, but stimulated by hMLH1/c-Abl/p73alpha/GADD45alpha retrograde signaling.

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Available from: Julio C. Morales, Mar 05, 2014
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    • "p73 and GADD45 are upregulated by MR-dependent ABL. It has been also shown that MR-dependent intrinsic apoptosis is p53-independent but stimulated by MLH1/ABL/p73/GADD45 retrograde signaling 12. p73, which is involved in MR was the only gene in this category that was upregulated after 212Pb-TCMC-trastuzumab therapy with a calculated 8.3-fold increase compared to 1.1-fold decrease after 212Pb-TCMC-HuIgG therapy. "
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    • "This finding suggests that there is a split in the methylator-induced response downstream of Chk1 such that p50 specifically mediates a cytotoxic pathway. Interestingly, a separation of methylator-induced killing from checkpoint response has also been described for the p53 ortholog, p73 (Li et al., 2008). "
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    • "Preclinical colon cancer c-Abl activates p73␣/GADD45␣, leading to apoptosis in response to DNA mismatch repair Li et al., 2008 Preclinical colon cancer c-Abl activates p73␣/GADD45␣, leading to G2 arrest after induction of DNA mismatch repair Wagner et al., 2008 Preclinical breast cancer ephrin B2/ephrin B4 suppress breast cancer tumorigenicity via activation of a c-Abl/Crk/MMP-2-signaling axis Noren et al., 2006 Preclinical thyroid cancer imatinib enhances thyroid cancer cell motility in response to HGF Frasca et al., 2001 Preclinical breast cancer activated c-Abl suppresses oncogenic TGF-␤ signaling, inhibits EMT and reverts breast cancer tumorigenicity in vitro and in vivo Allington et al., 2009 Clinical phase I breast cancer imatinib offered no clinical benefit in PDGF receptor-positive metatastic breast cancer Cristofanilli et al., 2008 Clinical phase II breast cancer imatinib provided no therapeutic benefit against invasive breast cancer patients Modi et al., 2005 Clinical phase II breast cancer imatinib and capecitabine treatment failed to improve the clinical course of metastatic breast cancer patients Chew et al., 2008 Clinical phase I/II prostate cancer imatinib administration either alone or in combination promoted disease progression and severe toxicity Lin et al., 2006, 2007a Clinical phase II pancreatic cancer imatinib administration fails to offer any therapeutic protection against pancreatic cancer Chen et al., 2006; Gharibo et al., 2008 EGFR = Epidermal growth factor receptor; HER2 = human epidermal growth factor receptor 2; IGF-1 = insulin growth factor 1; MMP-2 = matrix metalloproteinase 2; HGF = hepatocyte growth factor; PDGF = platelet-derived growth factor. of TGF-␤ behavior during tumorigenesis is known as the 'TGF-␤ paradox', whose eventual interpretation and translation holds the key to developing novel chemotherapies capable of preferentially targeting the oncogenic activities of TGF-␤ [Schiemann, 2007]. An important consequence of TGF-␤ signaling is its potential to induce EMT, a process whereby immotile, polarized epithelial cells transdifferentiate into highly motile, apolar fibroblastoid-like cells [Heldin et al., 2009; Wendt et al., 2009a; Xu et al., 2009]. "
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