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Negative regulation of TSC1-TSC2 by mammalian D-type cyclins.

The metazoan cell cycle is driven by the timely and composite activities of cyclin-dependent kinases (CDKs). Among these, cyclin D- and cyclin E-dependent kinases phosphorylate the pRb family proteins during G(1) phase of the cell cycle and thereby advance cells beyond the restriction point. Increasing evidence suggests that cyclin D-dependent kinases might affect events other than Rb pathway-mediated entry into S phase, such as accumulation of cell mass. However, little is known about cyclin D activity toward Rb-independent pathway(s) or non-pRb substrates. In this article, we show that the tumor suppressor TSC2 is a cyclin D binding protein. Coexpression of cyclin D1-CDK4/6 in cultured cells leads to increased phosphorylation and decreased detection of both TSC2 and TSC1, and promotes the phosphorylation of the mTOR substrates, 4E-BP1 and S6K1, two key effectors of cell growth that are negatively regulated by the TSC1-TSC2 complex. At the cellular level, ectopic expression of cyclin D1 restores the cell size decrease caused by TSC1-TSC2 expression. Intriguingly, down-regulation of TSC proteins was also observed by the expression of a mutant cyclin D1 that is unable to bind to CDK4/6, or by the coexpression of cyclin D1 with either an INK4 inhibitor or with catalytically inactive CDK6, indicating that cyclin D may regulate TSC1-TSC2 independently of CDK4/6. Together, these observations suggest that mammalian D-type cyclins participate in cell growth control through negative regulation of TSC1-TSC2 function.

Pubmed ID: 16357142

Authors

  • Zacharek SJ
  • Xiong Y
  • Shumway SD

Journal

Cancer research

Publication Data

December 15, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: CA68377

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Bone Neoplasms
  • Carrier Proteins
  • Cells, Cultured
  • Cyclin D1
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6
  • Cyclin-Dependent Kinase Inhibitor p16
  • G1 Phase
  • Gene Expression Regulation
  • Humans
  • Kidney
  • Osteosarcoma
  • Phosphoproteins
  • Phosphorylation
  • Retinoblastoma Protein
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Tumor Suppressor Proteins