title: Targeted disruption of Bcl-xL in mouse keratinocytes inhibits both UVB- and chemically induced skin carcinogenesis.
abstract: Bcl-x(L) is one of several antiapoptotic proteins regulated by signal transducer and activator of transcription 3 (Stat3). We have recently shown that Stat3 is required for chemically induced and ultraviolet B (UVB)-induced skin carcinogenesis. In this study, the functional role of Bcl-x(L) in skin carcinogenesis was investigated using skin-specific Bcl-x(L)-deficient mice. In this model, Bcl-x(L) expression is disrupted in the basal compartment of mouse epidermis using the bovine keratin 5 (K5) promoter to drive expression of Cre recombinase (K5.Cre x Bcl-x(L) (fl/fl) mice). A significant increase in apoptosis induced by either UVB irradiation or 7,12-dimethylbenz[a]anthracene (DMBA) treatment was observed in the epidermis of Bcl-x(L)-deficient mice. Furthermore, an increase in apoptotic cells was noted in hair follicle keratinocytes, including those located in the bulge region. Cell proliferation was not affected by Bcl-x(L) deficiency following exposure to either UVB or 12-O-tetradecanoylphorbol-13-acetate (TPA). Bcl-x(L)-deficient mice were more resistant than wild-type controls to skin tumor development with delayed onset and reduced number of tumors using either UVB or the DMBA/TPA two-stage regimen. Moreover, Bcl-2, Mcl-1, and survivin protein levels were increased in the epidermis of Bcl-x(L)-deficient mice in the absence of stimuli. Furthermore, levels of these antiapoptotic proteins were also high in skin tumors from Bcl-x(L)-deficient mice that developed in response to either UVB or two-stage carcinogenesis protocols. Collectively, these studies demonstrate that Bcl-x(L) plays a role early in skin carcinogenesis through its anti-apoptotic functions to enhance survival of keratinocytes, including bulge region keratinocyte stem cells, following DNA damage.
authors.affiliation: Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA.
authors.forename: Dae Joon
authors.initials: DJ
authors.lastname: Kim
authors.forename: Ken
authors.initials: K
authors.lastname: Kataoka
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Sano
authors.forename: Kevin
authors.initials: K
authors.lastname: Connolly
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kiguchi
authors.forename: John
authors.initials: J
authors.lastname: DiGiovanni
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002478:Cells, Cultured; D005260:Female; D007124:Immunoenzyme Techniques; D019426:Integrases / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced / Q000473:pathology / Q000517:prevention & control*; D012878:Skin Neoplasms / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D014466:Ultraviolet Rays; D051020:bcl-X Protein / Q000502:physiology*
chemical_list: C494812:Bcl2l1 protein, mouse; D002273:Carcinogens; D051020:bcl-X Protein; D015127:9,10-Dimethyl-1,2-benzanthracene; C045073:Cre recombinase; D019426:Integrases