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ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability

Oncogene volume 30, pages 3745–3754 (2011)Cite this article

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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.

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Acknowledgements

This work was supported by DOE grant (#DE-FG02-06ER64186-17) to DAB, a DOD BCRP pre-doctoral fellowship (W81XWH-06-0748) to EMG and a DOD PCRP post-doctoral fellowship (X8IXWH-09-1-0168) to XL. We are grateful to the Robert B and Virginia Payne Endowment for support of this work. We also thank the support received from the SAIR NIH U24 grant CA126608 and the Imaging Shared Resource of the Simmons Cancer Center. This is CSCN #024 and used the Flow Cytometry and Biostatistics cores of the Simmons Comprehensive Cancer Center.

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  1. E M Goetz and B Shankar: These authors contributed equally to this work.

Authors and Affiliations

  1. Departments of Oncology, Pharmacology, and Radiation Oncology, Laboratory of Molecular Stress Responses, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

    E M Goetz, B Shankar, Y Zou, J C Morales, X Luo, S Araki & D A Boothman

  2. Department of Neuro-Oncology, Program in Cell Stress and Cancer Nanomedicine, Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA

    R Bachoo

  3. Department of Pediatrics, Department of Biochemistry and Molecular Biology, Herman B Wells Center for Pediatrics Research, Indiana University Simon Cancer Center, Indiana University School of Medicine, Indianapolis, IN, USA

    L D Mayo

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  1. E M Goetz
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Correspondence to D A Boothman.

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Goetz, E., Shankar, B., Zou, Y. et al. ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability. Oncogene 30, 3745–3754 (2011). https://doi.org/10.1038/onc.2011.92

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