Ca2+ and BMP-6 signaling regulate E2F during epidermal keratinocyte differentiation
Ca2+ and BMP-6 signaling regulate E2F during epidermal keratinocyte differentiation
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DOI：
10.1074/jbc.m100780200
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发表时间：
2001-06-29
影响因子：
4.8
通讯作者：
Dagnino, L
中科院分区：
文献类型：
--
作者：
D'Souza, SJA;Pajak, A;Dagnino, L
表皮由鳞状上皮组成，由定向干细胞不断补充，其可以自我更新或分化。我们先前证明了E2 F基因在发育中的表皮中差异表达（Dagnino，L.，弗莱角J.，Bartley，S. M.，Farnham，P.，加利，B。L.，和菲利普斯，R. A. 04 The Dog（1997）8，553-563）。因此，我们推测，各种E2 F蛋白可能发挥不同的生长调节作用，在未分化的干细胞和终末分化的角质形成细胞。为了进一步了解E2 F基因在表皮形态发生中的功能，我们检测了未分化培养的小鼠原代角质形成细胞或用Ca 2+或BMP-6诱导分化的细胞中E2 F因子的表达、调节和蛋白质-蛋白质相互作用（（B）在bar 1下（m）在bar形态发生下（p）在bar rotein下（6）在bar下）。我们发现两种分化剂的E2 F调节模式相似，并证明了未分化增殖细胞中E2 F-1、-2和-3表达向终末分化角质形成细胞中E2 F-5表达的转变。通过转化生长因子-β抑制角质形成细胞增殖并没有提高E2 F-5蛋白水平，这表明这种反应是特异性的分化，而不是可逆的细胞周期退出。E2 F-5上调还伴随着含有E2 F5、p130和组蛋白脱乙酰酶（HDAC）1的异聚核复合物的形成。E2 F5的过表达以HDAC依赖的方式特异性抑制未分化角质形成细胞的DNA合成，表明E2 F-5（.）p130（.）HDAC 1复合物可能参与响应分化刺激的角质形成细胞从细胞周期的永久退出。
The epidermis consists of a squamous epithelium continuously replenished by committed stem cells, which can either self-renew or differentiate. We demonstrated previously that E2F genes are differentially expressed in developing epidermis (Dagnino, L., Fry, C. J., Bartley, S. M., Farnham, P., Gallie, B. L., and Phillips, R. A. (1997) Cell Growth Differ. 8, 553-563). Thus, we hypothesized that various E2F proteins likely play distinct growth regulatory roles in the undifferentiated stem cells and in terminally differentiated keratinocytes. To further understand the function of E2F genes in epidermal morphogenesis, we have examined the expression, regulation, and protein-protein interactions of E2F factors in undifferentiated cultured murine primary keratinocytes or in cells induced to differentiate with Ca2+ or BMP-6 ((b) under bar one (m) under bar orphogenetic (p) under bar (p) under bar rotein (6) under bar). We find similar patterns of E2F regulation with both differentiating agents and demonstrate a switch in expression from E2F-1, -2, and -3 in undifferentiated, proliferating cells to E2F-5 in terminally differentiated keratinocytes. Inhibition of keratinocyte proliferation by transforming growth factor-beta did not enhance E2F-5 protein levels, suggesting that this response is specific to differentiation rather than reversible cell cycle withdrawal. E2F-5 up-regulation is also accompanied by formation of heteromeric nuclear complexes containing E2F5, p130, and histone deacetylase (HDAC) 1. Overexpression of E2F5 specifically inhibited DNA synthesis in undifferentiated keratinocytes in an HDAC-dependent manner, suggesting that E2F-5(.)p130(.)HDAC1 complexes are likely involved in the permanent withdrawal from the cell cycle of keratinocytes responding to differentiation stimuli.