Tumor suppression by p27Kip1 and p21Cip1 during chemically induced skin carcinogenesis.
p27Kip1 and p21Cip1 are cyclin dependent kinase inhibitors which can arrest cell proliferation and p27 is a tumor suppressor gene. To address the mechanism of tumor suppression by p27 and to determine if p21 has a tumor suppressor phenotype, we utilized the two stage skin carcinogenesis model on p27 and p21 knockout mice. In this model, initiation, which involves mutation of H-ras induced by DMBA, can be distinguished from promotion induced by TPA, and progression to carcinoma. The mean number of papillomas did not differ between p27-/- and control littermates, but papilloma growth rate was increased and carcinomas developed earlier. Thus, p27 deficiency did not enhance initiation, but resulted in more rapid clonal expansion of initiated cells during promotion. TPA treatment reduced p27 expression in keratinocytes also supporting a role for p27 during promotion. Tumors from p27-/- mice contained mutant H-ras indicating that p27 deficiency did not substitute for mutant ras and further, that during ras driven tumor growth, p27 is partially antagonistic since its removal led to faster growth. The treated p27-/- mice also developed intestinal adenomas. p21-/- mice did not display a significant increase in tumor numbers, growth rate or progression to carcinomas and these tumors also had mutated H-ras. Carcinomas from p21-/- mice were more poorly differentiated with a high frequency of anaplastic spindle cell carcinomas. Thus p21 deficiency mainly resulted in higher grade undifferentiated tumors.
Philipp
J
J
Fred Hutchinson Cancer Research Center, 1100 Fairview N., Seattle, Washington, WA 98109, USA.
Vo
K
K
Gurley
K E
KE
Seidel
K
K
Kemp
C J
CJ
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000236:Adenoma; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002277:Carcinoma / Q000139:chemically induced; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D011905:Genes, ras; D007414:Intestinal Neoplasms; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D010212:Papilloma / Q000139:chemically induced; D012878:Skin Neoplasms / Q000139:chemically induced*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D025521:Tumor Suppressor Proteins
D002273:Carcinogens; C493957:Cdkn1a protein, mouse; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D008869:Microtubule-Associated Proteins; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015127:9,10-Dimethyl-1,2-benzanthracene; D018844:Cyclin-Dependent Kinases; D013755:Tetradecanoylphorbol Acetate