Cdk4 deficiency inhibits skin tumor development but does not affect normal keratinocyte proliferation.
Most human tumors have mutations that result in deregulation of the cdk4/cyclin-Ink4-Rb pathway. Overexpression of D-type cyclins or cdk4 and inactivation of Ink4 inhibitors are common in human tumors. Conversely, lack of cyclin D1 expression results in significant reduction in mouse skin and mammary tumor development. However, complete elimination of tumor development was not observed in these models, suggesting that other cyclin/cdk complexes play an important role in tumorigenesis. Here we described the effects of cdk4 deficiency on mouse skin proliferation and tumor development. Cdk4 deficiency resulted in a 98% reduction in the number of tumors generated through the two-stage carcinogenesis model. The absence of cdk4 did not affect normal keratinocyte proliferation and both wild-type and cdk4 knockout epidermis are equally affected after topical treatment with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA), resulting in epidermal hyperplasia. In similar fashion, cdk4 knockout keratinocytes proliferated well in an in vivo model of wound-induced proliferation. Biochemical studies in mouse epidermis showed that cdk6 activity increased twofold in cdk4-deficient mice compared to wild-type siblings. These results suggest that therapeutic approaches to inhibit cdk4 activity could provide a target to inhibit tumor development with minimal or no effect in normal tissue.
Rodriguez-Puebla
Marcelo L
ML
Science Park-Research Division, The University of Texas, M. D. Anderson Cancer Center, Smithville, Texas 78957, USA. marcelo@rodriguez-puebla.org
Miliani de Marval
Paula L
PL
LaCava
Margaret
M
Moons
David S
DS
Kiyokawa
Hiroaki
H
Conti
Claudio J
CJ
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002455:Cell Division / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000172:deficiency / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins; D012878:Skin Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D002273:Carcinogens; D011518:Proto-Oncogene Proteins; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D013755:Tetradecanoylphorbol Acetate