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

64Citations
Citations of this article
55Readers
Mendeley users who have this article in their library.

Abstract

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 G1 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. ©2005 American Association for Cancer Research.

Cite

CITATION STYLE

APA

Zacharek, S. J., Xiong, Y., & Shumway, S. D. (2005). Negative regulation of TSC1-TSC2 by mammalian D-type cyclins. Cancer Research, 65(24), 11354–11360. https://doi.org/10.1158/0008-5472.CAN-05-2236

Register to see more suggestions

Mendeley helps you to discover research relevant for your work.

Already have an account?

Save time finding and organizing research with Mendeley

Sign up for free