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

E. M. Goetz, B. Shankar, Y. Zou, J. C. Morales, X. Luo, S. Araki, R. Bachoo, L. D. Mayo, D. A. Boothman

Research output: Contribution to journalArticle

28 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3745-3754
Number of pages10
JournalOncogene
Volume30
Issue number35
DOIs
StatePublished - Sep 1 2011

Fingerprint

Clusterin
Ataxia Telangiectasia
Somatomedins
DNA Damage
Phosphotransferases
Ionizing Radiation
Cytotoxins
Insulin-Like Growth Factor I
Colonic Neoplasms
Protein Kinases
Neoplasms
Glycoproteins
DNA

Keywords

  • ATM
  • genetic instability
  • IGF-1
  • ionizing radiation
  • p53
  • secretory clusterin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Goetz, E. M., Shankar, B., Zou, Y., Morales, J. C., Luo, X., Araki, S., ... Boothman, D. A. (2011). ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability. Oncogene, 30(35), 3745-3754. https://doi.org/10.1038/onc.2011.92

ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability. / Goetz, E. M.; Shankar, B.; Zou, Y.; Morales, J. C.; Luo, X.; Araki, S.; Bachoo, R.; Mayo, L. D.; Boothman, D. A.

In: Oncogene, Vol. 30, No. 35, 01.09.2011, p. 3745-3754.

Research output: Contribution to journalArticle

Goetz, EM, Shankar, B, Zou, Y, Morales, JC, Luo, X, Araki, S, Bachoo, R, Mayo, LD & Boothman, DA 2011, 'ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability', Oncogene, vol. 30, no. 35, pp. 3745-3754. https://doi.org/10.1038/onc.2011.92
Goetz, E. M. ; Shankar, B. ; Zou, Y. ; Morales, J. C. ; Luo, X. ; Araki, S. ; Bachoo, R. ; Mayo, L. D. ; Boothman, D. A. / ATM-dependent IGF-1 induction regulates secretory clusterin expression after DNA damage and in genetic instability. In: Oncogene. 2011 ; Vol. 30, No. 35. pp. 3745-3754.
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