An unexpected role for keratin 10 end domains in susceptibility to skin cancer.
Keratin 10 (K10) is a type I keratin that is expressed in post-mitotic suprabasal keratinocytes of the skin. Based on cell culture experiments and transgenic mouse studies, it has been proposed that K10 suppresses cell proliferation and tumor formation in the skin. Furthermore, the ability of K10 to suppress cell proliferation was mapped to its unique N- and C-terminal protein domains. In the present study, we modified the endogenous keratin 14 (K14) gene of mice using a knock-in approach to encode a chimeric keratin that consists of the K14 rod domain fused to the K10 head and tail domains (K1014chim). This transgene was expressed in the basal layer of the epidermis and the outer root sheath of hair follicles. Unexpectedly, we found that the K10 end domains had no effect on basal keratinocyte proliferation in vivo. Moreover, when subjected to a chemical skin carcinogenesis protocol, papilloma formation in mutant mice was accelerated instead of being inhibited. Our data suggest that the increased tumor susceptibility of K1014chim mice is in part due to a suppression of apoptosis in mutant keratinocytes. Our results support the notion that intermediate filaments, in addition to their function as cytoskeletal components, affect tumor susceptibility of epithelial cells.
Chen
Jiangli
J
Department of Dermatology, Baylor College of Medicine, Houston, TX 77030, USA.
Cheng
Xing
X
Merched-Sauvage
Maria
M
Caulin
Carlos
C
Roop
Dennis R
DR
Koch
Peter J
PJ
D000818:Animals; D017209:Apoptosis; D001665:Binding Sites; D018929:Cell Culture Techniques; D002465:Cell Movement; D049109:Cell Proliferation; D004198:Disease Susceptibility / Q000378:metabolism / Q000503:physiopathology; D020287:In Situ Nick-End Labeling; D007382:Intermediate Filaments / Q000378:metabolism; D053550:Keratin-10 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D014466:Ultraviolet Rays
D053547:Keratin-14; D053550:Keratin-10