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 G2 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 G2 arrest and cell death remains undefined. Since MMR-dependent phosphorylation and stabilization of p53 were noted, we investigated
its role(s) in G2 arrest and apoptosis. Loss of p53 function by E6 expression, dominant-negative p53, or stable p53 knockdown failed to prevent
MMR-dependent G2 arrest, apoptosis, or lethality. MMR-dependent c-Abl-mediated p73α and GADD45α protein up-regulation after MNNG exposure
prompted us to examine c-Abl/p73α/GADD45α signaling in cell death responses. STI571 (Gleevec™, a c-Abl tyrosine kinase inhibitor)
and stable c-Abl, p73α, and GADD45α knockdown prevented MMR-dependent apoptosis. Interestingly, stable p73α knockdown blocked
MMR-dependent apoptosis, but not G2 arrest, thereby uncoupling G2 arrest from lethality. Thus, MMR-dependent intrinsic apoptosis is p53-independent, but stimulated by hMLH1/c-Abl/p73α/GADD45α
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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    ABSTRACT: Recent studies have demonstrated that therapy with (212) Pb-TCMC-trastuzumab resulted in (1) induction of apoptosis, (2) G2/M arrest, and (3) blockage of double-strand DNA damage repair in LS-174T i.p. (intraperitoneal) xenografts. To further understand the molecular basis of the cell killing efficacy of (212) Pb-TCMC-trastuzumab, gene expression profiling was performed with LS-174T xenografts 24 h after exposure to (212) Pb-TCMC-trastuzumab. DNA damage response genes (84) were screened using a quantitative real-time polymerase chain reaction array (qRT-PCR array). Differentially regulated genes were identified following exposure to (212) Pb-TCMC-trastuzumab. These included genes involved in apoptosis (ABL, GADD45α, GADD45γ, PCBP4, and p73), cell cycle (ATM, DDIT3, GADD45α, GTSE1, MKK6, PCBP4, and SESN1), and damaged DNA binding (DDB) and repair (ATM and BTG2). The stressful growth arrest conditions provoked by (212) Pb-TCMC-trastuzumab were found to induce genes involved in apoptosis and cell cycle arrest in the G2/M phase. The expression of genes involved in DDB and single-strand DNA breaks was also enhanced by (212) Pb-TCMC-trastuzumab while no modulation of genes involved in double-strand break repair was apparent. Furthermore, the p73/GADD45 signaling pathway mediated by p38 kinase signaling may be involved in the cellular response, as evidenced by the enhanced expression of genes and proteins of this pathway. These results further support the previously described cell killing mechanism by (212) Pb-TCMC-trastuzumab in the same LS-174T i.p. xenograft. Insight into these mechanisms could lead to improved strategies for rational application of radioimmunotherapy using α-particle emitters.
    Full-text · Article · Oct 2013 · Cancer Medicine
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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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    ABSTRACT: The functional significance of the signaling pathway induced by O(6)-methylguanine (O(6)-MeG) lesions is poorly understood. Here, we identify the p50 subunit of NF-κB as a central target in the response to O(6)-MeG and demonstrate that p50 is required for S(N)1-methylator-induced cytotoxicity. In response to S(N)1-methylation, p50 facilitates the inhibition of NF-κB-regulated antiapoptotic gene expression. Inhibition of NF-κB activity is noted to be an S phase-specific phenomenon that requires the formation of O(6)-MeG:T mismatches. Chk1 associates with p50 following S(N)1-methylation, and phosphorylation of p50 by Chk1 results in the inhibition of NF-κB DNA binding. Expression of an unphosphorylatable p50 mutant blocks inhibition of NF-κB-regulated antiapoptotic gene expression and attenuates S(N)1-methylator-induced cytotoxicity. While O(6)-MeG:T-induced, p50-dependent signaling is not sufficient to induce cell death, this pathway sensitizes cells to the cytotoxic effects of DNA breaks.
    Full-text · Article · Dec 2011 · Molecular cell
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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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    ABSTRACT: Transforming growth factor-β (TGF-β) normally inhibits breast cancer development by preventing mammary epithelial cell (MEC) proliferation, by inducing MEC apoptosis, and by creating cell microenvironments that maintain MEC homeostasis and prevent their uncontrolled growth and motility. Mammary tumorigenesis elicits dramatic alterations in MEC architecture and microenvironment integrity, which collectively counteract the tumor-suppressing activities of TGF-β and enable its stimulation of breast cancer invasion and metastasis. How malignant MECs overcome the cytostatic actions imposed by normal microenvironments and TGF-β, and how abnormal microenvironments conspire with TGF-β to stimulate the development and progression of mammary tumors remains largely undefined. These knowledge gaps have prevented science and medicine from implementing treatments effective in simultaneously targeting abnormal cellular microenvironments, and in antagonizing the oncogenic activities of TGF-β in developing and progressing breast cancers. c-Abl is a ubiquitously expressed nonreceptor protein tyrosine kinase that essentially oversees all aspects of cell physiology, including the regulation of cell proliferation, migration and adhesion, as well as that of cell survival. Thus, the biological functions of c-Abl are highly reminiscent of those attributed to TGF-β, including the ability to function as either a suppressor or promoter of tumorigenesis. Interestingly, while dysregulated Abl activity clearly promotes tumorigenesis in hematopoietic cells, an analogous role for c-Abl in regulating solid tumor development, including those of the breast, remains controversial. Here, we review the functions of c-Abl in regulating breast cancer development and progression, and in alleviating the oncogenic activities of TGF-β and its stimulation of epithelial-mesenchymal transition during mammary tumorigenesis.
    Preview · Article · Nov 2010 · Cells Tissues Organs
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