Keratinocyte G2/M growth arrest by 1,25-dihydroxyvitamin D3 is caused by Cdc2 phosphorylation through Wee1 and Myt1 regulation

J Invest Dermatol. 2004 Jun;122(6):1356-64. doi: 10.1111/j.0022-202X.2004.22522.x.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / metabolism*
  • Calcitriol / pharmacology*
  • Calcium Channel Agonists / pharmacology*
  • Cell Cycle Proteins*
  • Cells, Cultured
  • Cyclin B / metabolism
  • Cyclin B1
  • G2 Phase / drug effects
  • Gene Expression / drug effects
  • Humans
  • Keratinocytes / cytology*
  • Keratinocytes / drug effects
  • Keratinocytes / metabolism
  • Membrane Proteins
  • Mitosis / drug effects
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation / drug effects
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*

Substances

  • CCNB1 protein, human
  • Calcium Channel Agonists
  • Cell Cycle Proteins
  • Cyclin B
  • Cyclin B1
  • Membrane Proteins
  • Nuclear Proteins
  • Protein-Tyrosine Kinases
  • WEE1 protein, human
  • PKMYT1 protein, human
  • Protein Serine-Threonine Kinases
  • CDC2 Protein Kinase
  • Calcitriol