Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38

Rosner, Margit; Hofer, Katja; Kubista, Marion; Hengstschläger, Markus

doi:10.1038/sj.onc.1206776

Cited by 92 publications

(75 citation statements)

References 66 publications

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“…Thus, a primary role for TSC1 and TSC2 appears to be in restricting cell and organ size. The role of TSC1/2 in restricting cell growth is evolutionarily conserved, as overexpression of TSC1 or TSC2 in cultured mammalian cells also reduces cell size (Inoki et al, 2003b;Rosner et al, 2003). Genetic epistasis experiments placed TSC1/2 in the Drosophila insulin signaling pathway: TSC1 and TSC2 were found to be epistatic (dominant) to the insulin receptor, PTEN, and dAkt, but dS6K was found to be epistatic to TSC1/ 2 (Gao and Pan, 2001;Potter et al, 2001;Tapon et al, 2001a;Radimerski et al, 2002).…”

Section: Tsc1/2 a Novel Negative Regulator Of Tormentioning

confidence: 99%

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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Cell growth (an increase in cell mass and size through macromolecular biosynthesis) and cell cycle progression are generally tightly coupled, allowing cells to proliferate continuously while maintaining their size. The target of rapamycin (TOR) is an evolutionarily conserved kinase that integrates signals from nutrients (amino acids and energy) and growth factors (in higher eukaryotes) to regulate cell growth and cell cycle progression coordinately. In mammals, TOR is best known to regulate translation through the ribosomal protein S6 kinases (S6Ks) and the eukaryotic translation initiation factor 4E-binding proteins. Consistent with the contribution of translation to growth, TOR regulates cell, organ, and organismal size. The identification of the tumor suppressor proteins tuberous sclerosis1 and 2 (TSC1 and 2) and Ras-homolog enriched in brain (Rheb) has biochemically linked the TOR and phosphatidylinositol 3-kinase (PI3K) pathways, providing a mechanism for the crosstalk that occurs between these pathways. TOR is emerging as a novel antitumor target, since the TOR inhibitor rapamycin appears to be effective against tumors resulting from aberrantly high PI3K signaling. Not only may inhibition of TOR be effective in cancer treatment, but rapamycin is an FDA-approved immunosuppressive and cardiology drug. We review here what is known (and not known) about the function of TOR in cellular and animal physiology.

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Section: Tsc1/2 a Novel Negative Regulator Of Tormentioning

confidence: 99%

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

2004

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“…Cells were analysed on a Beckton Dickinson FACScan (Beckton Dickinson, San Jose, CA, USA). For the analyses of the amount of subG1 cells after transient transfection GFP-positive cells were selectively gated and DNA distribution was analysed (Rosner et al, 2003). To monitor nuclear chromatin condensation and cell death Hoechst 33258 (Sigma) and propidium iodide (Sigma) were added directly to the culture medium to final concentrations of 5 and 2 mg ml À1 , respectively.…”

Section: Methodsmentioning

confidence: 99%

Ras mediates cell survival by regulating tuberin

et al. 2007

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Mutational activation of Ras promotes oncogenesis by controlling cell cycle regulation and cell survival. Rasmediated activation of both, the PI3K/AKT pathway and the MEK/ERK pathway, can trigger downregulation of the function of tuberin to block the activities of mTOR and p70S6K. Here we demonstrate that Ras-induced cell survival is accompanied by upregulation of p70S6K activity. Ras harbors the potential to negatively affect tuberin-induced apoptosis and p70S6K inactivation. These effects of Ras were found to depend on its potential to regulate the MEK/ERK pathway. Experiments using tuberin-negative fibroblasts revealed that the potential of Ras to counteract apoptosis depends on functional tuberin. Taken together, we provide evidence that the function of Ras to trigger inactivation of tuberin plays a major role in the regulation of cell survival upon mutational activation of the oncogene Ras. This is the first description of a functional interaction between the tumor suppressor tuberin and the oncogene Ras in regulating apoptosis.

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“…Proteins were run on an SDS-polyacrylamide gel and transferred to nitrocellulose. Blots were stained with Ponceau S to visualize the loaded protein (23). Immunodetection was performed using anti-tuberin antibody (tuberin C-20; Santa Cruz Biotechnology), anti-hamartin antibody (2197; kindly provided by M. Nellist), anti-p27 antibody (p27 C-19; Santa Cruz Biotechnology), anti-FLAG antibody (M2, Sigma), anti-Skp2 antibody (H-435; Santa Cruz Biotechnology), anti-cyclin A antibody (C-19; Santa Cruz Biotechnology), anti-cyclin D1 antibody (M-20; Santa Cruz Biotechnology), anti-cdk2 antibody (M-2; Santa Cruz Biotechnology), or anti-␣-tubulin antibody (Ab-1, Oncogene).…”

Section: Methodsmentioning

confidence: 99%

“…Starting with equal cell numbers (harvesting and reseeding), the cell pools were grown under G418 selection for 7 days, and cell numbers were determined on the CASY cell counter and analyzer. For these analyses, cells growing in Petri dishes were washed with buffer and harvested by trypsinization (12,23,24).…”

Section: Methodsmentioning

confidence: 99%

Tuberin Binds p27 and Negatively Regulates Its Interaction with the SCF Component Skp2

Rosner

Hengstschläger

2004

Journal of Biological Chemistry

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TSC1 (tuberous sclerosis complex 1) encoding hamartin and TSC2 encoding tuberin are tumor suppressor genes responsible for the autosomal dominantly inherited disease tuberous sclerosis. These genes have been demonstrated to negatively regulate cell cycle progression, the activity of cdk2, and the degradation of the cyclin-dependent kinase inhibitor p27. To date, the underlying molecular mechanism remains elusive. Here, we show that tuberin binds to p27. Whereas tuberin also binds p27 in TSC1-negative cells, hamartin does not bind p27 without tuberin. p27 protein levels are regulated through ubiquitin-dependent degradation. Skp2 is the F-box protein, which, together with other proteins, forms an SCF (Skp1/cullin/F-box protein)-type E3 ubiquitin ligase complex whose task is to target p27 for degradation by the proteasome. We found that neither tuberin nor hamartin are in a complex with Skp2. Tuberin does not affect Skp2 protein levels, and the SCF Skp2 ubiquitin ligase does not regulate tuberin stability. But binding of tuberin to p27 sequesters p27 from Skp2 accompanied by an up-regulation of the p27 interaction with cdk2. Skp2-induced p27 degradation and cell cycle progression is abolished by tuberin s protective binding to p27. This work, the first description of the direct interaction of a tumor suppressor protein with p27, provides a molecular explanation for the effects of tuberous sclerosis complex genes on the cell cycle and demonstrates a new aspect of the SCF Skp2 -mediated regulation of p27 stability.

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Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38

Cited by 92 publications

References 66 publications

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

Ras mediates cell survival by regulating tuberin

Tuberin Binds p27 and Negatively Regulates Its Interaction with the SCF Component Skp2

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