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.
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
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
Cancer Res.
Date: Dec. 15, 2005
PubMed ID: 16357142
View in: Pubmed Google Scholar
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