The ink4a/arf tumor suppressors cooperate with p21cip1/waf in the processes of mouse epidermal differentiation, senescence, and carcinogenesis.
In mammalian cells, cell cycle withdrawal is a prerequisite for terminal differentiation. Accordingly, in most tissues, including epidermis, the expression of the cyclin-dependent kinase inhibitors increases during differentiation. However, the actual role of cyclin-dependent kinase inhibitors is unclear. Different aspects of epidermal growth and differentiation in ink4a(Delta2,3)-null, p21-null, and ink4a(Delta2,3)/p21-doubly deficient mice were studied. Altered differentiation and decreased age-related senescence were found in the epidermis of ink4a(Delta2,3)/p21-null mice and, to a lesser extent, in ink4a(Delta2,3)- and p21-null mice. ink4a(Delta2,3)/p21-null primary keratinocytes underwent cell cycle arrest upon calcium or transforming growth factor-beta treatment, but failed to differentiate. This differentiation deficiency was not observed in p21- or ink4a(Delta2,3)-deficient keratinocytes. Upon infection with a v-Ha-ras-coding retrovirus, wild-type keratinocytes displayed features indicative of premature cell senescence. In p21- or ink4a(Delta2,3)-deficient keratinocytes, only a partial response was observed. ink4a(Delta2,3)/p21-deficient keratinocytes did not display senescent features, but showed increased tumorigenic potential upon injection into nude mice. These results indicate that ink4a/arf and cip1/waf genes cooperate to allow normal keratinocyte differentiation and that the absence of both favors malignant transformation.
Paramio
J M
JM
Cell, Molecular Biology, and Gene Therapy Project, CIEMAT, Avenida Complutense 22, E-28040 Madrid, Spain. jesusm.paramio@ciemat.es
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Ruiz
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Martin-Caballero
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Martinez
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Serrano
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Jorcano
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D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002471:Cell Transformation, Neoplastic; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000502:physiology*; D000078404:Epidermal Cells; D005455:Fluorescent Antibody Technique; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL
C493957:Cdkn1a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins