p21WAF1/Cip1 suppresses keratinocyte differentiation independently of the cell cycle through transcriptional up-regulation of the IGF-I gene.
p21 plays a dual role in keratinocyte growth and differentiation control. It restricts the number of keratinocyte stem cell populations while inhibiting the later stages of differentiation independently of the cell cycle. The molecular/biochemical mechanism for the differentiation suppressive function of p21 is unknown. Here we show that elevated p21 expression leads to activation of MAPK family members in a keratinocyte-specific and cell cycle-independent manner, and up-regulation of MAPK activity can explain the inhibitory effects of p21 on differentiation. p21 induces transcription of several genes with MAPK activation potential. Although several of these genes are induced by p21 in a MAPK-dependent manner, expression of IGF-I is induced upstream of MAPK activation. IGF-I stimulation is by itself sufficient to cause MAPK activation and inhibit differentiation and suppression of IGF-I signaling by knock down of the cognate receptor (IGF-R1), diminishing the ability of p21 to activate MAPK and suppress differentiation. Thus, in keratinocytes, the ability of p21 to suppress differentiation can be explained by cell type-specific activation of the MAPK cascade by transcriptional up-regulation of the IGF-I gene.
Devgan
Vikram
V
Cutaneous Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA.
Nguyen
Bach-Cuc
BC
Oh
Heysun
H
Dotto
G Paolo
GP
D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism / Q000502:physiology*; D004789:Enzyme Activation; D004817:Epidermis / Q000378:metabolism; D005786:Gene Expression Regulation; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis* / Q000235:genetics; D015603:Keratinocytes / Q000166:cytology* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007334:Insulin-Like Growth Factor I