title: Negative regulation of the FOXO3a transcription factor by mTORC2 induces a pro-survival response following exposure to ultraviolet-B irradiation.
abstract: Exposure to ultraviolet-B (UVB) irradiation, the principal cause of non-melanoma skin cancer (NMSC), activates both the rapamycin-sensitive mammalian target of rapamycin complex 1 (mTORC1) and the rapamycin-resistant mTORC2. We have previously reported that UVB-induced keratinocyte survival is dependent on mTORC2, though the specific mechanism is not well understood. FOXO3a is an important transcription factor involved in regulating cell survival. The activity of FOXO3a is reduced as a result of protein kinase B (AKT/PKB) activation, which is downstream of mTORC2; however, the specific function of FOXO3a during UVB-induced apoptosis is unclear. In this study, we establish that in cells with wild-type mTORC2 activity, FOXO3a is quickly phosphorylated in response to UVB and sequestered in the cytoplasm. In contrast, loss of mTORC2 causes FOXO3a to be localized to the nucleus and sensitizes cells to UVB-induced apoptosis. Furthermore, this sensitization is rescued by knockdown of FOXO3a. Taken together, these studies provide strong evidence that inhibition of mTORC2 enhances UVB-induced apoptosis in a FOXO3a-dependent manner, and suggest that FOXO3a activation by mTORC2 inhibitors may be a valuable chemopreventive target in NMSC.
authors.affiliation: Department of Cellular and Molecular Physiology, The Penn State University College of Medicine, Hershey, PA 17033, United States. Electronic address: rpf10@psu.edu.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Feehan
authors.affiliation: Department of Cellular and Molecular Physiology, The Penn State University College of Medicine, Hershey, PA 17033, United States. Electronic address: lms17@psu.edu.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shantz
mesh_terms: D017209:Apoptosis / Q000528:radiation effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism / Q000528:radiation effects; D002470:Cell Survival / Q000528:radiation effects; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D017353:Gene Deletion; D055785:Gene Knockdown Techniques; D006801:Humans; D000076225:Mechanistic Target of Rapamycin Complex 2; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation / Q000528:radiation effects; D015398:Signal Transduction / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D046912:Multiprotein Complexes; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Apoptosis; Cancer chemoprevention; FOXO; Keratinocyte; Mammalian target of rapamycin (mTOR); UVB