Calcineurin regulates cyclin D1 accumulation in growth-stimulated fibroblasts.

Journal Article (Journal Article)

Calcium (Ca(2+)) and calmodulin (CaM) are required for progression of mammalian cells from quiescence into S phase. In multiple cell types, cyclosporin A causes a G(1) cell cycle arrest, implicating the serine/threonine phosphatase calcineurin as one Ca(2+)/CaM-dependent enzyme required for G(1) transit. Here, we show, in diploid human fibroblasts, that cyclosporin A arrested cells in G(1) before cyclin D/cdk4 complex activation and retinoblastoma hyperphosphorylation. This arrest occurred in early G(1) with low levels of cyclin D1 protein. Because cyclin D1 mRNA was induced normally in the cyclosporin A-treated cells, we analyzed the half-life of cyclin D1 in the presence of cyclosporin A and found no difference from control cells. However, cyclosporin A treatment dramatically reduced cyclin D1 protein synthesis. Although these pharmacological experiments suggested that calcineurin regulates cyclin D1 synthesis, we evaluated the effects of overexpression of activated calcineurin on cyclin D1 synthesis. In contrast to the reduction of cyclin D1 with cyclosporin A, ectopic expression of calcium/calmodulin-independent calcineurin promoted synthesis of cyclin D1 during G(1) progression. Therefore, calcineurin is a Ca(2+)/CaM-dependent target that regulates cyclin D1 accumulation in G(1).

Full Text

Duke Authors

Cited Authors

  • Kahl, CR; Means, AR

Published Date

  • April 2004

Published In

Volume / Issue

  • 15 / 4

Start / End Page

  • 1833 - 1842

PubMed ID

  • 14767060

Pubmed Central ID

  • PMC379279

International Standard Serial Number (ISSN)

  • 1059-1524

Digital Object Identifier (DOI)

  • 10.1091/mbc.e03-10-0730


  • eng

Conference Location

  • United States