Hamartin and Tuberin Interaction With the G2/M Cyclin-Dependent Kinase CDK1 and Its Regulatory Cyclins A and B

Catania, Michael; Mischel, Paul S.; Vinters, Harry V.

doi:10.1093/jnen/60.7.711

Cited by 57 publications

(23 citation statements)

References 31 publications

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“…Additionally, the studies in Drosophila also suggest the potential involvement of other cyclins in negatively regulating TSC1-TSC2. Consistent with this, we have detected interactions between TSC2 and cyclins A, B, and E (data not shown), and interactions between TSC2 and cyclin A, cyclin B, and CDK1 have been reported previously (42,61).…”

Section: Discussionsupporting

confidence: 92%

Negative Regulation of TSC1-TSC2 by Mammalian D-Type Cyclins

Zacharek

Shumway

2005

Cancer Research

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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. (Cancer Res 2005; 65(24): 11354-60)

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Section: Discussionsupporting

confidence: 92%

Negative Regulation of TSC1-TSC2 by Mammalian D-Type Cyclins

Zacharek

Shumway

2005

Cancer Research

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“…Binding of unique co-regulators can lead to tissue-specific responses (50 -52). The tuberin molecule is a large 180-kDa tumor suppressor protein with a variety of protein-interacting domains (19,26,28,(53)(54)(55). We have previously shown that tuberin can modulate ligand-induced steroid/nuclear receptor-mediated transcription in vitro (24 -26).…”

Section: Discussionmentioning

confidence: 99%

Estrogen-induced Smooth Muscle Cell Growth Is Regulated by Tuberin and Associated with Altered Activation of Platelet-derived Growth Factor Receptor-β and ERK-1/2

Finlay

York

Karas

et al. 2004

Journal of Biological Chemistry

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The mechanisms that regulate the diverse responses to estrogen (E 2 ) are unknown. Loss of function of the tuberous sclerosis 2 gene (TSC2), a tumor suppressor gene, has been associated with a growth-promoting effect of E 2 . We hypothesized that tuberin, the protein product of TSC2, binds to estrogen receptors (ER) and regulates the growth effect of E 2 . An in vivo association between full-length tuberin and ER␣ was observed in HEK 293 cells and ELT-3 smooth muscle cells. In contrast, poor association was observed between tuberin and ER␤. Complex formation with ER␣ and the C-terminal end of tuberin was also observed in vivo and in vitro, indicating that binding between ER␣ and tuberin occurs at the C-terminal end of the tuberin molecule. We examined the effect of tuberin expression in ELT-3 smooth

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“…The increase in threonine-proline phosphorylation of hamartin was evident 8 h after release when 48% of the cells were in the G 2 /M phase and then decreased at 16 and 24 h when 27 and 19% of the cells were in the G 2 /M phase, respectively. been previously shown to interact with CDK1 and cyclin B1 (39). To determine whether a threonine-proline residue of hamartin was phosphorylated, the hamartin immunoprecipitate was immunoblotted with a phosphothreonine-proline antibody.…”

Section: Figmentioning

confidence: 99%

Cell Cycle-regulated Phosphorylation of Hamartin, the Product of the Tuberous Sclerosis Complex 1 Gene, by Cyclin-dependent Kinase 1/Cyclin B

Astrinidis

Senapedis

Coleman

et al. 2003

Journal of Biological Chemistry

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Tuberous sclerosis complex is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, and benign tumors of the brain, skin, heart, and kidneys. Hamartin and tuberin, the products of the TSC1 and TSC2 genes, respectively, form a complex and inhibit signaling by the mammalian target of rapamycin. Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G 2 /M arrest and during the G 2 /M phase of a normal cell cycle. In vitro assays showed that cyclin-dependent kinase 1 phosphorylates hamartin at three sites, one of which (Thr 417 ) is in the hamartintuberin interaction domain. Tuberin interacts with phosphohamartin, and tuberin expression attenuates the phosphorylation of exogenous hamartin. Hamartin with alanine mutations in the three cyclin-dependent kinase 1 phosphorylation sites increased the inhibition of p70S6 kinase by the hamartin-tuberin complex. These findings support a model in which phosphorylation of hamartin regulates the function of the hamartin-tuberin complex during the G 2 /M phase of the cell cycle. Tuberous sclerosis complex (TSC)1 is a tumor suppressor gene syndrome whose manifestations can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. Mutations in two genes, TSC1 on chromosome 9q34 (1) and TSC2 on chromosome 16p13 (2), cause TSC. Tuberin, the TSC2 gene product, and hamartin, the TSC1 gene product, are known to interact (3, 4) and appear to function as a complex.Hamartin and tuberin function in multiple cellular pathways in mammalian cells, including vesicular trafficking (5), regulation of the G 1 phase of the cell cycle (6 -10), steroid hormone regulation (11), and Rho activation (12, 13). Tuberin has a highly conserved domain with homology to rap1 GTPaseactivating protein, and it has been shown to possess GTPaseactivating protein activity for Rap1A (14), Rab5 (5), and Rheb (15-18). Hyperphosphorylation of p70S6 kinase (p70S6K) and/or its substrate ribosomal protein S6 occurs in cells lacking hamartin from a murine model of TSC1 (19), in cells lacking tuberin from the Eker rat model of TSC2 (20,21), and in tumor cells containing TSC2 mutations (22), demonstrating that the hamartin-tuberin complex negatively regulates p70S6K. Studies in Drosophila (9, 10, 23) and mammalian cells suggest that regulation of p70S6K by the hamartin-tuberin complex is mediated by the mammalian target of rapamycin (mTOR) (24, 25), although controversy exists (26).Tuberin is phosphorylated by the kinase Akt (protein kinase B) (24, 27-30). Phosphorylation of tuberin by Akt negatively regulates inhibition of p70S6K by tuberin. Tuberin is also a substrate of the p38 and MK2 kinase cascade (31), mediating its interaction with 14-3-3 (32-34). Here, we report that endogenous hamartin is phosphorylated during G 2 /M, demonstrating for the first time that hamartin, like tuberin, is regulated by phosphorylation. Results from both in vitro and in vivo experiments indicate that hamartin ...

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Hamartin and Tuberin Interaction With the G2/M Cyclin-Dependent Kinase CDK1 and Its Regulatory Cyclins A and B

Cited by 57 publications

References 31 publications

Negative Regulation of TSC1-TSC2 by Mammalian D-Type Cyclins

Negative Regulation of TSC1-TSC2 by Mammalian D-Type Cyclins

Estrogen-induced Smooth Muscle Cell Growth Is Regulated by Tuberin and Associated with Altered Activation of Platelet-derived Growth Factor Receptor-β and ERK-1/2

Cell Cycle-regulated Phosphorylation of Hamartin, the Product of the Tuberous Sclerosis Complex 1 Gene, by Cyclin-dependent Kinase 1/Cyclin B

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