p21WAF1/Cip1 suppresses keratinocyte differentiation independently of the cell cycle through transcriptional up-regulation of the IGF-I gene
p21WAF1/Cip1 suppresses keratinocyte differentiation independently of the cell cycle through transcriptional up-regulation of the IGF-I gene
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DOI：
10.1074/jbc.m604684200
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发表时间：
2006-10-13
影响因子：
4.8
通讯作者：
Dotto, G. Paolo
中科院分区：
文献类型：
--
作者：
Devgan, Vikram;Nguyen, Bach-Cuc;Dotto, G. Paolo
P21在角质形成细胞的生长和分化调控中具有双重作用。它限制角质形成干细胞群体的数量，同时抑制独立于细胞周期的后期分化。P21抑制分化的分子/生化机制尚不清楚。在这里，我们发现p21的高表达导致MAPK家族成员以角质形成细胞特异性和细胞周期非依赖性的方式被激活，而MAPK活性的上调可以解释p21对分化的抑制作用。P21可诱导几个具有MAPK激活潜能的基因转录。虽然这些基因中的几个是由p21以MAPK依赖的方式诱导的，但IGF-I的表达是在MAPK激活的上游诱导的。IGF-I刺激本身就足以引起MAPK的激活，并通过下调同源受体(IGF-R1)来抑制分化和抑制IGF-I信号的分化，从而降低p21激活MAPK和抑制分化的能力。因此，在角质形成细胞中，p21抑制分化的能力可以通过IGF-I基因转录上调而激活MAPK级联的细胞类型来解释。
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.