ArticleProceedings of the National Academy of Sciences of the United States of America1998
Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2.
Article in Proceedings of the National Academy of Sciences of the United States of America, 1998. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 176 citations in OpenAlex.
- The role of TSC2 in breast cancer: a literature review.Frontiers in oncology · 2023Review
- The Tuberin and Cyclin B1 complex functions as a novel G2/M sensor of serum conditions and Akt signaling.PloS one · 2019Article
- mTORC1 promotes proliferation of immature Schwann cells and myelin growth of differentiated Schwann cells.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- TSC loss distorts DNA replication programme and sensitises cells to genotoxic stress.Oncotarget · 2016Article
- Hyperactivation of Akt/mTOR and deficiency in tuberin increased the oxidative DNA damage in kidney cancer patients with diabetes.Oncotarget · 2014Article
- SRC kinase is a novel therapeutic target in lymphangioleiomyomatosis.Cancer research · 2014Article
- Tumor suppressors TSC1 and TSC2 differentially modulate actin cytoskeleton and motility of mouse embryonic fibroblasts.PloS one · 2014Article
- Merging high-quality biochemical fractionation with a refined flow cytometry approach to monitor nucleocytoplasmic protein expression throughout the unperturbed mammalian cell cycle.Nature protocols · 2013Article
- TSC2 modulates cell adhesion and migration via integrin-α1β1.American journal of physiology. Lung cellular and molecular physiology · 2012Article
- p27kip1 protein levels reflect a nexus of oncogenic signaling during cell transformation.The Journal of biological chemistry · 2012Article
- Staying alive: metabolic adaptations to quiescence.Cell cycle (Georgetown, Tex.) · 2012Review
- ERK crosstalks with 4EBP1 to activate cyclin D1 translation during quinol-thioether-induced tuberous sclerosis renal cell carcinoma.Toxicological sciences : an official journal of the Society of Toxicology · 2011Article
- Tuberous sclerosis presenting with confusion and agitation.Clinical medicine (London, England) · 2011Article
- Rho-associated kinase connects a cell cycle-controlling anchorage signal to the mammalian target of rapamycin pathway.The Journal of biological chemistry · 2011Article
- Therapeutic role of mammalian target of rapamycin (mTOR) inhibition in preventing epileptogenesis.Neuroscience letters · 2011Review
- Phosphorylated p27Kip1 on Thr157 is an important prognosis in human hepatocellular carcinoma in vivo and in vitro.Medical oncology (Northwood, London, England) · 2011Article
- Effects of prolactin on TSC2-null Eker rat cells and in pulmonary lymphangioleiomyomatosis.American journal of respiratory and critical care medicine · 2010Article
- AMPK-mediated phosphorylation of murine p27 at T197 promotes binding of 14-3-3 proteins and increases p27 stability.Molecular carcinogenesis · 2010Article
- Lymphangioleiomyomatosis and TSC2-/- cells.Lymphatic research and biology · 2010Review
- Mammalian target of rapamycin (mTOR) inhibition as a potential antiepileptogenic therapy: From tuberous sclerosis to common acquired epilepsies.Epilepsia · 2010Review
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Authors and funding
3 authors at 2 institutions in 2 countries.
Funding
Abstract
Tuberous sclerosis is an autosomal dominant disorder characterized by the development of aberrant growths in many tissues and organs. Linkage analysis revealed two disease-determining genes on chromosome 9 and chromosome 16. The tuberous sclerosis complex gene-2 (TSC2) on chromosome 16 encodes the tumor suppressor protein tuberin. We have shown earlier that loss of TSC2 is sufficient to induce quiescent cells to enter the cell cycle. Here we show that TSC2-negative fibroblasts exhibit a shortened G1 phase. Although the expression of cyclin E, cyclin A, p21, or Cdc25A is unaffected, TSC2-negative cells express much lower amounts of the cyclin-dependent kinase (CDK) inhibitor p27 because of decreased protein stability. In TSC2 mutant cells the amount of p27 bound to CDK2 is diminished, accompanied with elevated kinase activity. Ectopic expression studies revealed that the aforementioned effects can be reverted by transfecting TSC2 in TSC2-negative cells. High ectopic levels of p27 have cell cycle inhibitory effects in TSC2-positive cells but not in TSC2-negative counterparts, although the latter still depend on CDK2 activity. Loss of TSC2 induces soft agar growth of fibroblasts, a process that cannot be inhibited by high levels of p27. Both phenotypes of TSC2-negative cells, their resistance to the activity of ectopic p27, and the instability of endogenous p27, could be explained by our observation that the nucleoprotein p27 is mislocated into the cytoplasm upon loss of TSC2. These findings provide insights into the molecular mechanism of how loss of TSC2 induces cell cycle entry and allow a better understanding of its tumor suppressor function.
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