Cyclin D1 downregulation is important for permanent cell cycle exit and initiation of differentiation induced by anchorage-deprivation in human keratinocytes.
Cyclin D1 downregulation is important for permanent cell cycle exit and initiation of differentiation induced by anchorage-deprivation in human keratinocytes.
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DOI：
10.1002/jcb.21978
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发表时间：
2009-01-01
影响因子：
4
通讯作者：
Rice, Robert H.
中科院分区：
文献类型：
--
作者：
Nishi, Kayoko;Inoue, Hirokazu;Schnier, Joachim B.;Rice, Robert H.
为了了解永久细胞周期退出和分化之间的关系，永生化角质形成细胞系，IK和鳞状细胞癌，SCC 9在通过锚定剥夺诱导分化过程中进行了比较。当置于悬浮培养物中时，该IK细胞在2天内迅速丧失了几乎所有重新启动生长的能力，同时表达分化特异性蛋白质、转氨酶（TGK）和外皮蛋白。这些细胞迅速经历G1期细胞周期停滞，磷酸化RB完全消失。相反，SCC 9细胞既不显示TGK表达，也不显示外皮蛋白增加。它们降低其集落形成能力的速度要慢得多，这与磷酸化RB的逐渐减少很好地协调，证明了对集落形成能力丧失和细胞周期退出的显著抗性。根据，细胞周期蛋白D1，细胞周期蛋白依赖性激酶（CDK）4/6的磷酸化RB的正调节剂大幅下降，在锚定剥夺的SIK，但不是在SCC 9细胞。内源性细胞周期蛋白D1敲低SCC 9细胞的siRNA增强了锚定剥夺过程中集落形成能力的丧失。相反，在IK细胞和另一种永生化角质形成细胞系HaCaT中，细胞周期蛋白D1的表达部分阻止了它们的集落形成能力的丧失。细胞周期蛋白D1过表达拮抗角蛋白10在悬浮HaCaT细胞的表达。结果表明，细胞周期蛋白D1下调的重要性，正确启动角质形成细胞分化。
To understand the relationship between permanent cell cycle exit and differentiation the immortalized keratinocyte cell line, SIK and the squamous cell carcinoma, SCC9 were compared during differentiation induced by anchorage-deprivation. The SIK cells when placed in suspension culture promptly lost almost all ability to reinitiate growth by 2 days concomitantly expressing the differentiation specific proteins, transglutaminase (TGK) and involucrin. These cells rapidly underwent G1 cell cycle arrest with complete disappearance of phosphorylated RB. In contrast SCC9 cells neither showed TGK expression nor increase in involucrin. They decreased their colony-forming ability much more slowly, which coordinated well with a gradual decrease in phosphorylated RB, demonstrating the significant resistance to loss of colony-forming ability and cell cycle exit. In accordance, cyclin D1, a positive regulator of cyclin-dependent kinase (CDK) 4/6 which phosphorylates RB decreased drastically in anchorage deprived SIK but not in SCC9 cells. Endogenous cyclin D1 knockdown in SCC9 cells by siRNA enhanced loss of the colony-forming ability during anchorage-deprivation. Conversely enforced expression of cyclin D1 in SIK cells and in another immortalized keratinocyte cell line, HaCaT, partly prevented loss of their colony-forming abilities. Cyclin D1 overexpression antagonized Keratin 10 expression in suspended HaCaT cells. The result demonstrates the importance of cyclin D1 down regulation for proper initiation of keratinocyte differentiation.
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