Bax gene disruption alters the epidermal response to ultraviolet irradiation and in vivo induced skin carcinogenesis.
Bcl-2 family member proteins are differentially expressed in skin and in non-melanoma skin cancer (NMSC). To elucidate the contribution of bcl-2 and bax proteins to epidermal differentiation and skin carcinogenesis, we investigated keratinocyte proliferation, differentiation and tumourigenesis in bcl-2(-/-) and bax(-/-) mice. The rate and pattern of proliferation and spontaneous cell death in the bcl-2(-/-) and bax(-/-) mice were not different from control mice. The epidermis of bcl-2(-/-) and bax(-/-) expressed sightly higher levels of cytokeratin 1 and loricrin compared to control littermates. The apoptotic response to ultraviolet-induced genotoxic stress was assessed by quantitating TUNEL positive cells. Bax(-/-) keratinocytes showed a significant resistance to UV-induced cell death compared to control mice. The life-span of bcl-2(-/-) mice precluded an assessment of bcl-2 gene disruption on in vivo tumourigenesis. A significant increase in tumour incidence was observed in bax(-/-) mice compared to control mice in two-step chemical carcinogenesis studies. These findings suggest that bcl-2 and bax gene products may be important determinants of normal keratinocyte differentiation and response to genotoxic stress in vivo, and indicate that bax may provide a tumour suppressor effect during skin carcinogenesis.
Cho
S H
SH
Department of Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.
Delehedde
M
M
Rodriguez-Villanueva
J
J
Brisbay
S
S
McDonnell
T J
TJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology; D002454:Cell Differentiation; D000078404:Epidermal Cells; D004817:Epidermis / Q000528:radiation effects*; D019254:Genes, bcl-2 / Q000235:genetics*; D015151:Immunoblotting; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology / Q000528:radiation effects*; D007633:Keratins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D012878:Skin Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000503:physiopathology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; D002273:Carcinogens; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C064554:loricrin; D015127:9,10-Dimethyl-1,2-benzanthracene; D007633:Keratins; D013755:Tetradecanoylphorbol Acetate