Stress and IGF-I differentially control cell fate through mammalian target of rapamycin (mTOR) and retinoblastoma protein (pRB)

Melissa Popowski, Heather A. Ferguson, Amy M. Sion, Erich Koller, Erik Knudsen, Carla L. Van Den Berg

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Significant discoveries have recently contributed to our knowledge of intracellular growth factor and nutrient signaling via mTOR (mammalian target of rapamycin). This signaling pathway is essential in cellular metabolism and cell survival by enhancing protein translation through phosphorylation of 4EBP-1 and p70S6K. Growth factors like insulin-like growth factor-I induce mTOR to prevent cell death during cellular stress. Agents targeting mTOR are of major interest as anticancer agents. We show here, using human breast cancer cells, that certain types of stress activate mTOR leading to 4E-BP1 and p70S6K phosphorylation. UV treatment increased phosphorylation of the translation inhibitor eIF2α, suggesting a potential mechanism for UV activation of Akt and mTOR. c-Myc, a survival protein regulated by cap-dependent protein translation, increased with IGF-I treatment, but this response was not inhibited by rapamycin. Additionally, UV treatment potently increased c-Myc degradation, which was reduced by co-treatment with the proteasomal inhibitor, MG-132. Together, these data suggest that protein translation does not strongly mediate cell survival in these models. In contrast, the phosphorylation status of retinoblastoma protein (pRB) was mediated by mTOR through its inhibitory effects on phosphatase activity. This effect was most notable during DNA damage and rapamycin treatment. Hypophosphorylated pRB was susceptible to inactivation by caspase-mediated cleavage, resulting in cell death. Reduction of pRB expression inhibited IGF-I survival effects. Our data support an important role of phosphatases and pRB in IGF-I/mTOR-mediated cell survival. These studies provide new directions in optimizing anticancer efficacy of mTOR inhibitors when used in combination with DNA-damaging agents.

Original languageEnglish (US)
Pages (from-to)28265-28273
Number of pages9
JournalJournal of Biological Chemistry
Volume283
Issue number42
DOIs
StatePublished - Oct 17 2008

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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