Targeted disruption of Bcl-xL in mouse keratinocytes inhibits both UVB- and chemically induced skin carcinogenesis
✍ Scribed by Dae Joon Kim; Ken Kataoka; Shigetoshi Sano; Kevin Connolly; Kaoru Kiguchi; John DiGiovanni
- Publisher
- John Wiley and Sons
- Year
- 2009
- Tongue
- English
- Weight
- 645 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0899-1987
- DOI
- 10.1002/mc.20527
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✦ Synopsis
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 × Bcl‐x 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. © 2009 Wiley‐Liss, Inc.