title: ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability.
abstract: Secretory clusterin (sCLU) is a stress-induced, pro-survival glycoprotein elevated in early-stage cancers, in particular in APC/Min-defective colon cancers. sCLU is upregulated after exposure to various cytotoxic agents, including ionizing radiation (IR), leading to a survival advantage. We found that stimulation of insulin-like growth factor-1 (IGF-1) and IGF-1R protein kinase signaling was required for sCLU induction after IR exposure. Here, we show that activation of Ataxia telangiectasia-mutated kinase (ATM) by endogenous or exogenous forms of DNA damage was required to relieve basal repression of IGF-1 transcription by the p53/NF-YA complex, leading to sCLU expression. Although p53 levels were stabilized and elevated after DNA damage, dissociation of NF-YA, and thereby p53, from the IGF-1 promoter resulted in IGF-1 induction, indicating that NF-YA was rate limiting. Cells with elevated endogenous DNA damage (deficient in H2AX, MDC1, NBS1, mTR or hMLH1) or cells exposed to DNA-damaging agents had elevated IGF-1 expression, resulting in activation of IGF-1R signaling and sCLU induction. In contrast, ATM-deficient cells were unable to induce sCLU after DNA damage. Our results integrate DNA damage resulting from genetic instability, IR, or chemotherapeutic agents, to ATM activation and abrogation of p53/NF-YA-mediated IGF-1 transcriptional repression, that induces IGF-1-sCLU expression. Elucidation of this pathway should uncover new mechanisms for cancer progression and reveal new targets for drug development to overcome resistance to therapy.
authors: Departments of Oncology, Pharmacology, and Radiation Oncology, Laboratory of Molecular Stress Responses, University of Texas Southwestern Medical Center at Dallas, TX, USA.
authors: E M
authors: EM
authors: Goetz
authors: B
authors: B
authors: Shankar
authors: Y
authors: Y
authors: Zou
authors: J C
authors: JC
authors: Morales
authors: X
authors: X
authors: Luo
authors: S
authors: S
authors: Araki
authors: R
authors: R
authors: Bachoo
authors: L D
authors: LD
authors: Mayo
authors: D A
authors: DA
authors: Boothman
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D023081:CCAAT-Binding Factor / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D051152:Clusterin / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D023081:CCAAT-Binding Factor; D018797:Cell Cycle Proteins; D051152:Clusterin; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D007334:Insulin-Like Growth Factor I; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases