title: Epidermal Rac1 regulates the DNA damage response and protects from UV-light-induced keratinocyte apoptosis and skin carcinogenesis.
abstract: Non-melanoma skin cancer (NMSC) is the most common type of cancer. Increased expression and activity of Rac1, a small Rho GTPase, has been shown previously in NMSC and other human cancers; suggesting that Rac1 may function as an oncogene in skin. DMBA/TPA skin carcinogenesis studies in mice have shown that Rac1 is required for chemically induced skin papilloma formation. However, UVB radiation by the sun, which causes DNA damage, is the most relevant cause for NMSC. A potential role of Rac1 in UV-light-induced skin carcinogenesis has not been investigated so far. To investigate this, we irradiated mice with epidermal Rac1 deficiency (Rac1-EKO) and their controls using a well-established protocol for long-term UV-irradiation. Most of the Rac1-EKO mice developed severe skin erosions upon long-term UV-irradiation, unlike their controls. These skin erosions in Rac1-EKO mice healed subsequently. Surprisingly, we observed development of squamous cell carcinomas (SCCs) within the UV-irradiation fields. This shows that the presence of Rac1 in the epidermis protects from UV-light-induced skin carcinogenesis. Short-term UV-irradiation experiments revealed increased UV-light-induced apoptosis of Rac1-deficient epidermal keratinocytes in vitro as well as in vivo. Further investigations using cyclobutane pyrimidine dimer photolyase transgenic mice revealed that the observed increase in UV-light-induced keratinocyte apoptosis in Rac1-EKO mice is DNA damage dependent and correlates with caspase-8 activation. Furthermore, Rac1-deficient keratinocytes showed reduced levels of p53, γ-H2AX and p-Chk1 suggesting an attenuated DNA damage response upon UV-irradiation. Taken together, our data provide direct evidence for a protective role of Rac1 in UV-light-induced skin carcinogenesis and keratinocyte apoptosis probably through regulating mechanisms of the DNA damage response and repair pathways.
authors.affiliation: Department of Dermatology, University of Cologne, Kerpener Strasse 62, Cologne 50937, Germany.
authors.forename: Jayesh
authors.initials: J
authors.lastname: Deshmukh
authors.affiliation: Department of Dermatology, University of Cologne, Kerpener Strasse 62, Cologne 50937, Germany.
authors.forename: Ruth
authors.initials: R
authors.lastname: Pofahl
authors.affiliation: Department of Dermatology, University of Cologne, Kerpener Strasse 62, Cologne 50937, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D063646:Carcinogenesis / Q000528:radiation effects; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004260:DNA Repair / Q000528:radiation effects; D006801:Humans; D015603:Keratinocytes / Q000473:pathology / Q000528:radiation effects; D051379:Mice; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D014466:Ultraviolet Rays; D020830:rac1 GTP-Binding Protein / Q000235:genetics*
chemical_list: C107953:RAC1 protein, human; D020830:rac1 GTP-Binding Protein