title: Activation of the PI3K/Akt/mTOR and MAPK Signaling Pathways in Response to Acute Solar-Simulated Light Exposure of Human Skin.
abstract: The incidence of skin cancer is higher than all other cancers and continues to increase, with an average annual cost over $8 billion in the United States. As a result, identifying molecular pathway alterations that occur with UV exposure to strategize more effective preventive and therapeutic approaches is essential. To that end, we evaluated phosphorylation of proteins within the PI3K/Akt and MAPK pathways by immunohistochemistry in sun-protected skin after acute doses of physiologically relevant solar-simulated ultraviolet light (SSL) in 24 volunteers. Biopsies were performed at baseline, 5 minutes, 1, 5, and 24 hours after SSL irradiation. Within the PI3K/Akt pathway, we found activation of Akt (serine 473) to be significantly increased at 5 hours while mTOR (serine 2448) was strongly activated early and was sustained over 24 hours after SSL. Downstream, we observed a marked and sustained increase in phospho-S6 (serine 235/S236), whereas phospho-4E-BP1 (threonines 37/46) was increased only at 24 hours. Within the MAPK pathway, SSL-induced expression of phospho-p38 (threonine 180/tyrosine 182) peaked at 1 to 5 hours. ERK 1/2 was observed to be immediate and sustained after SSL irradiation. Phosphorylation of histone H3 (serine 10), a core structural protein of the nucleosome, peaked at 5 hours after SSL irradiation. The expression of both p53 and COX-2 was increased at 5 hours and was maximal at 24 hours after SSL irradiation. Apoptosis was significantly increased at 24 hours as expected and indicative of a sunburn-type response to SSL. Understanding the timing of key protein expression changes in response to SSL will aid in development of mechanistic-based approaches for the prevention and control of skin cancers.
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Yira
authors.initials: Y
authors.lastname: Bermudez
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Stratton
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Clara
authors.initials: C
authors.lastname: Curiel-Lewandrowski
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. The University of Arizona Cancer Center, Tucson, Arizona. Department of Surgery, University of Arizona, Tucson, Arizona.
authors.forename: James
authors.initials: J
authors.lastname: Warneke
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: George T
authors.initials: GT
authors.lastname: Bowden
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Sally E
authors.initials: SE
authors.lastname: Dickinson
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, Minnesota.
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Kathylynn
authors.initials: K
authors.lastname: Saboda
authors.affiliation: The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: Christine A
authors.initials: CA
authors.lastname: Brooks
authors.affiliation: George Mason University, Manassas, Virginia.
authors.forename: Emanuel F
authors.initials: EF
authors.lastname: Petricoin
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. Department of Surgery, University of Arizona, Tucson, Arizona.
authors.forename: Craig A
authors.initials: CA
authors.lastname: Hurst
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. The University of Arizona Cancer Center, Tucson, Arizona.
authors.forename: David S
authors.initials: DS
authors.lastname: Alberts
authors.affiliation: College of Medicine, University of Arizona, Tucson, Arizona. The University of Arizona Cancer Center, Tucson, Arizona. einspahr@email.arizona.edu.
authors.forename: Janine G
authors.initials: JG
authors.lastname: Einspahr
mesh_terms: D000368:Aged; D004307:Dose-Response Relationship, Radiation; D004890:Erythema / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000528:radiation effects; D012867:Skin / Q000378:metabolism* / Q000473:pathology / Q000528:radiation effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human