title: Insulin-like growth factor-1 receptor regulates repair of ultraviolet B-induced DNA damage in human keratinocytes in vivo.
abstract: The activation status of the insulin-like growth factor-1 receptor (IGF-1R) regulates the cellular response of keratinocytes to ultraviolet B (UVB) exposure, both in vitro and in vivo. Geriatric skin is deficient in IGF-1 expression resulting in an aberrant IGF-1R-dependent UVB response which contributes to the development of aging-associated squamous cell carcinoma. Furthermore, our lab and others have reported that geriatric keratinocytes repair UVB-induced DNA damage less efficiently than young adult keratinocytes. Here, we show that IGF-1R activation influences DNA damage repair in UVB-irradiated keratinocytes. Specifically, in the absence of IGF-1R activation, the rate of DNA damage repair following UVB-irradiation was significantly slowed (using immortalized human keratinocytes) or inhibited (using primary human keratinocytes). Furthermore, inhibition of IGF-1R activity in human skin, using either ex vivo explant cultures or in vivo xenograft models, suppressed DNA damage repair. Primary keratinocytes with an inactivated IGF-1R also exhibited lower steady-state levels of nucleotide excision repair mRNAs. These results suggest that deficient UVB-induced DNA repair in geriatric keratinocytes is due in part to silenced IGF-1R activation in geriatric skin and provide a mechanism for how the IGF-1 pathway plays a role in the initiation of squamous cell carcinoma in geriatric patients.
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Mathew M
authors.initials: MM
authors.lastname: Loesch
authors.affiliation: Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Ann E
authors.initials: AE
authors.lastname: Collier
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: David H
authors.initials: DH
authors.lastname: Southern
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Ward
authors.affiliation: Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, United States; Richard L. Roudebush V.A. Medical Center, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Sunil S
authors.initials: SS
authors.lastname: Tholpady
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Davina A
authors.initials: DA
authors.lastname: Lewis
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States; Richard L. Roudebush V.A. Medical Center, Indiana University School of Medicine, Indianapolis, IN, United States.
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
authors.affiliation: Department of Dermatology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Biochemistry & Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States. Electronic address: dspanda@iupui.edu.
authors.forename: Dan F
authors.initials: DF
authors.lastname: Spandau
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics / Q000528:radiation effects*; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects*; D007700:Kinetics; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism; D014466:Ultraviolet Rays; D023041:Xenograft Model Antitumor Assays
chemical_list: D017526:Receptor, IGF Type 1; D019098:Telomerase
keywords: IGF-1R; Keratinocyte; NER; UVB; Xenograft