Keratinocyte G2/M growth arrest by 1,25-dihydroxyvitamin D3 is caused by Cdc2 phosphorylation through Wee1 and Myt1 regulation
Keratinocyte G2/M growth arrest by 1,25-dihydroxyvitamin D3 is caused by Cdc2 phosphorylation through Wee1 and Myt1 regulation
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DOI：
10.1111/j.0022-202x.2004.22522.x
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发表时间：
2004-06-01
影响因子：
6.5
通讯作者：
Hashimoto, K
中科院分区：
文献类型：
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作者：
Dai, X;Yamasaki, K;Hashimoto, K
1，25-二羟基维生素D3（1，25 [OH]（2）VD 3）对角质形成细胞生长具有抗增殖作用，其衍生物用于治疗银屑病。以前有报道1，25 [OH]（2）VD 3不仅诱导细胞周期停滞在G 0/G1期，而且也诱导细胞周期停滞在G2/M期。然而，1，25 [OH]（2）VD 3诱导角质形成细胞G2/M期阻滞的机制尚未完全了解。10（-8）~ 10（-6）M 1，25 [OH]（2）VD 3对培养的正常人角质形成细胞Myt 1 mRNA的表达有促进作用，而对Wee 1 mRNA的表达无促进作用。有趣的是，在1，25 [OH]（2）VD 3处理后6 h至48 h，磷酸化Cdc 2的水平增加，尽管Cdc 2 mRNA的表达水平及其蛋白质的产生降低。1，25 [OH]（2）VD 3还降低了与Cdc 2形成复合物的cyclin B1的表达。这些数据表明，Myt 1和Wee 1的增加诱导Cdc 2磷酸化，导致G2/M期阻滞。总之，由于Wee 1和Myt 1的增加而诱导的Cdc 2磷酸化以及Cdc 2和细胞周期蛋白B1的减少参与了1，25 [OH]（2）VD 3诱导的角质形成细胞G2/M停滞。
1,25-dihydroxyvitamin D3 (1,25[OH](2)VD3) has an antiproliferative effect on keratinocyte growth, and its derivatives are used for the treatment of psoriasis. It was reported previously that 1,25[OH](2)VD3 induced cell cycle arrest not only at the G0/G1 phase but also at the G2/M phase. However, the mechanism of 1,25[OH](2)VD3-induced G2/M phase arrest in keratinocytes has not been fully understood. The addition of 10(-8) to 10(-6) M 1,25[OH](2)VD3 to cultured normal human keratinocytes enhanced the expression of Myt1 mRNA preceding Wee1 mRNA; 10(-6) M 1,25[OH](2)VD3 unregulated Myt1 mRNA from 6 h to 24 h and Wee1 mRNA from 12 to 48 h. Interestingly, the levels of phosphorylated Cdc2 were increased between 6 h and 48 h after 1,25[OH](2)VD3 treatment, although the expression levels of Cdc2 mRNA and its protein production were reduced. 1,25[OH](2)VD3 also decreased the expression of cyclin B1, which forms a complex with Cdc2. These data indicated that the increase of Myt1 and Wee1 induced the phosphorylation of Cdc2 leading to G2/M arrest. In conclusion, the induction of Cdc2 phosphorylation due to the increase of Wee1 and Myt1 as well as the reduction of Cdc2 and cyclin B1 are involved in 1,25[OH](2)VD3-induced G2/M arrest of keratinocytes.