A Calmodulin Binding Site in the Tuberous Sclerosis 2 Gene Product Is Essential for Regulation of Transcription Events and Is Altered by Mutations Linked to Tuberous Sclerosis and Lymphangioleiomyomatosis

Noonan, Daniel J.; Lou, Dingyuan; Griffith, Nicole; Vanaman, Thomas C.

doi:10.1006/abbi.2001.2682

Cited by 49 publications

(50 citation statements)

References 44 publications

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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%

“…Standard recombinant DNA technologies were utilized to develop mammalian expression constructs of TSC2 as previously described (20,24,26). The GST fusion constructs of TSC2 are described elsewhere (26).…”

Section: Plasmid Constructsmentioning

confidence: 99%

“…GST and GST-TSC2-C672 fusion proteins were prepared from BL21-RP Escherichia coli cells essentially as previously described (26). Pull-down assays were performed similar to previous studies (24).…”

Section: Protein Pull-down Assaysmentioning

confidence: 99%

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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

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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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Section: Discussionmentioning

confidence: 99%

Section: Plasmid Constructsmentioning

confidence: 99%

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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 putative GAP domain has been reported to increase the intrinsic GTPase activity of both Rab5 and Rap1A GTPases (20,21). Further downstream, tuberin modulates the transcriptional activity of AP1 and the steroid hormone receptor family (22)(23)(24). However, little else is known about how tuberin is regulated or about its other downstream signaling targets.…”

Section: Lymphangioleiomyomatosis (Lam)mentioning

confidence: 99%

Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

Goncharova¹,

Goncharov²,

Eszterhas³

et al. 2002

Journal of Biological Chemistry

395

166

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Although the cellular functions of TSC2 and its protein product, tuberin, are not known, somatic mutations in the TSC2 tumor suppressor gene are associated with tumor development in lymphangioleiomyomatosis (LAM). We found that ribosomal protein S6 (S6), which exerts translational control of protein synthesis and is required for cell growth, is hyperphosphorylated in the smooth muscle-like cell lesions of LAM patients compared with smooth muscle cells from normal human blood vessels and trachea. Smooth muscle (SM) cells derived from these lesions (LAMD-SM) also exhibited S6 hyperphosphorylation, constitutive activation of p70 S6 kinase (p70S6K), and increased basal DNA synthesis. In parallel, TSC2؊/؊ smooth muscle cells (ELT3) and TSC2؊/؊ epithelial cells (ERC15) also exhibited hyperphosphorylation of S6, constitutive activation of p70S6K, and increased basal DNA synthesis. Re-introduction of wild type tuberin into LAMD-SM, ELT3, and ERC15 cells abolished phosphorylation of S6 and significantly inhibited p70S6K activity and DNA synthesis. Rapamycin, an immunosuppressant, inhibited hyperphosphorylation of S6, p70S6K activation, and DNA synthesis in LAMD-SM cells. Interestingly, the basal levels of phosphatidylinositol 3-kinase, Akt/protein kinase B, and p42/p44 MAPK activation were unchanged in LAMD-SM and ELT3 cells relative to levels in normal human tracheal and vascular SM. These data demonstrate that tuberin negatively regulates the activity of S6 and p70S6K specifically, and suggest a potential mechanism for abnormal cell growth in LAM.

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“…As LAM is associated with oestrogen-mediated signalling events, it seemed probable that tuberin could have an impact on this signalling pathway. In 2002, Noonan et al 32 identified the sequence (amino-acids 1740-1755) that is capable of forming a basic amphipathic helix indicative of calmodulin (CaM)-binding domain. Deletion mutagenesis studies suggest that this CaM-binding domain is required for the modulation of steroid receptor function by tuberin and that mutations in this region may be involved in the pathology of TSC and LAM.…”

Section: Tuberinmentioning

confidence: 99%

Hamartin and tuberin: Working together for tumour suppression

Jóźwiak

2005

Intl Journal of Cancer

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TSC1 and TSC2 are two recently identified tumour suppressor genes encoding hamartin and tuberin, respectively, and involved in pathogenesis of tuberous sclerosis, neurological disorder connected with the development of hamartomas in numerous organ systems, including the brain, kidneys, heart and liver. Both protein products of TSC1 and TSC2 form an intracellular complex exerting GTPase-activating (GAP) activity towards a small G protein, Ras homologue enriched in brain (Rheb). Inhibition of Rheb is important for the regulation of mTOR pathway, while mutation of hamartin or tuberin results in uncontrolled cell cycle progression. Tuberin, possessing the Rheb-GAP domain, is phosphorylated by several kinases that confer the signals of growth factor stimulation or low cellular energy levels. Such a modification of tuberin influences its activity within the complex with hamartin and positively or negatively modulates mTOR-regulated protein translation and cellular proliferation. Current article describes biochemical properties of hamartin and tuberin, their known regulatory phosphorylation sites and binding partners. ' 2005 Wiley-Liss, Inc.

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A Calmodulin Binding Site in the Tuberous Sclerosis 2 Gene Product Is Essential for Regulation of Transcription Events and Is Altered by Mutations Linked to Tuberous Sclerosis and Lymphangioleiomyomatosis

Cited by 49 publications

References 44 publications

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

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

Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

Hamartin and tuberin: Working together for tumour suppression

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