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Cited by 72PI3K/AKT/mTOR signaling in cancerCancer-related Molecular PathwaysHippo pathway signaling and YAP/TAZ

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

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Zacharek, Sima J., Xiong, Yue, Shumway, Stuart D.·2005·Cancer Research
DOI 10.1158/0008-5472.can-05-2236
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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. (Cancer Res 2005; 65(24): 11354-60)

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  • PKR also controls the state of phosphorylation of TSC2 perhaps through the activation of the proteasomal degradation of cyclin D1 involved in the increased phosphorylation of TSC2 when it is associated to CDK4/6.

    “Thus, PKR also controls this state of phosphorylation of TSC2 perhaps through the activation of the proteasomal degradation of cyclin D1 involved in the increased phosphorylation of TSC2 when it is associated to CDK4/6 [139].”

    From PKR, the double stranded RNA‐dependent protein kinase as a critical target in Alzheimer's disease (2009) · cites this paper as [139]

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Cited by

Sorted by citations

Authors
Zacharek, S. J., Xiong, Y., & Shumway, S. D.
Affiliations
  • UNC Lineberger Comprehensive Cancer Center (US)
  • University of North Carolina at Chapel Hill (US)
ORCID
Venue
Cancer Research
Publisher
American Association for Cancer Research (AACR)
Published
2005-12-15
Volume
65
Issue
24
Pages
11354-11360
ISSN
  • 0008-5472 (ISSN-L)
  • 1538-7445
DOI
10.1158/0008-5472.can-05-2236
OpenAlex
W2131099175
Cited by
72
References
4
Citations by year
2026: 2 · 2025: 2 · 2024: 4 · 2023: 2 · 2022: 4 · 2021: 3 · 2020: 11 · 2019: 4 · 2018: 3 · 2017: 7 · 2016: 6 · 2015: 1 · 2014: 1 · 2013: 2 · 2012: 3
FWCI
1.00
Type
journal article
Language
en
Open access
Locations
  • Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Cancer Society
  • National Institutes of Health
  • National Cancer Institute (CA68377, R01CA068377)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
Keywords
TSC1, TSC2, D-type cyclins, cyclin D1, CDK4/6, mTOR signaling, 4E-BP1, S6K1, cell growth regulation, cell size, restriction point, tumor suppressor regulation
MeSH terms
Tuberous Sclerosis Complex 1 Protein, Tuberous Sclerosis Complex 2 Protein, Bone Neoplasms, Carrier Proteins, Cells, Cultured, Gene Expression Regulation, Humans, Kidney, Phosphoproteins, Phosphorylation, Osteosarcoma, Retinoblastoma Protein, G1 Phase, Cell Cycle Proteins, Cyclin D1, Cyclin-Dependent Kinase Inhibitor p16, Tumor Suppressor Proteins, Ribosomal Protein S6 Kinases, 70-kDa, Adaptor Proteins, Signal Transducing, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6

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