Keratinocyte G2/M growth arrest by 1,25-dihydroxyvitamin D3 is caused by Cdc2 phosphorylation through Wee1 and Myt1 regulation.
1,25-dihydroxyvitamin D3 (1,25[OH]2VD3) 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]2VD3 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]2VD3-induced G2/M phase arrest in keratinocytes has not been fully understood. The addition of 10(-8) to 10(-6) M 1,25[OH]2VD3 to cultured normal human keratinocytes enhanced the expression of Myt1 mRNA preceding Wee1 mRNA; 10(-6) M 1,25[OH]2VD3 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]2VD3 treatment, although the expression levels of Cdc2 mRNA and its protein production were reduced. 1,25[OH]2VD3 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]2VD3-induced G2/M arrest of keratinocytes.
Dai
Xiuju
X
Department of Dermatology, Ehime University School of Medicine, Ehime, Japan.
Yamasaki
Kenshi
K
Yang
Lujun
L
Sayama
Koji
K
Shirakata
Yuji
Y
Tokumara
Sho
S
Yahata
Yoko
Y
Tohyama
Mikiko
M
Hashimoto
Koji
K
D016203:CDC2 Protein Kinase / Q000378:metabolism*; D002117:Calcitriol / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D016195:G2 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015603:Keratinocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins; D008938:Mitosis / Q000187:drug effects; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*
C534699:CCNB1 protein, human; D002120:Calcium Channel Agonists; D018797:Cell Cycle Proteins; D019926:Cyclin B; D056744:Cyclin B1; D008565:Membrane Proteins; D009687:Nuclear Proteins; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C490679:PKMYT1 protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D002117:Calcitriol