Dysregulation of mTORC1 Signaling in Childhood Solid Tumors

The mTORC1 complex regulates cap-dependent translation, and is essential for cell proliferation. Nutrient deficiency, and hypoxia, conditions characteristic of solid tumors, suppress mTORC1 signaling, yet tumor cells maintain proliferation. We have examined the pathway by which hypoxia suppresses mTORC1 signaling and examined the consequences of maintained signaling under hypoxic conditions. Regulation of mTORC1 signaling was examined by phosphorylation of downstream substrates (4E-BP1 and S6 protein) in cell lines with or without ATM, as well as mutants defective in DNA damage repair (NBS1-/-), p53-/-, and REDD…