The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination

Benvenuto, Giovanna; Li, Shaowei; Brown, Samantha J.; Braverman, Richard; Vass, William C.; Cheadle, Jeremy P.; Halley, Dicky; Sampson, Julian R.; Wienecke, Ralf; DeClue, Jeffrey E.

doi:10.1038/sj.onc.1204009

Cited by 235 publications

(200 citation statements)

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“…Pathways in which tuberin, the TSC2 gene product, is believed to participate include vesicular trafficking (42) and cell cycle regulation (43,44). Hamartin, the TSC1 gene product, also regulates the cell cycle (45)(46)(47)(48) and affects focal adhesion formation via activation of the GTPase Rho (49). To date, no direct connections between the functions of hamartin and tuberin and the function of the VHL protein, pVHL, have been identified.…”

Section: Discussionmentioning

confidence: 99%

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

et al. 2002

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Tuberous sclerosis complex (TSC) is an autosomaldominant disorder characterized by seizures, mental retardation, autism, and tumors of multiple organs. Renal disease in TSC includes angiomyolipomas, cysts, and renal cell carcinomas. It is known that somatic mutations in the von Hippel Lindau (VHL) tumor suppressor gene occur in most clear cell renal carcinomas. To determine whether TSCassociated clear cell carcinomas also contain VHL mutations, we analyzed six tumors for loss of heterozygosity in the VHL gene region of chromosome 3p and for mutations in the VHL gene. Four of the patients were women between the ages of 34 and 68 years, and two were males under the age of 21 years. The loss of heterozygosity analysis was performed using polymorphic microsatellite markers, and the mutational analysis was performed using direct sequencing. Chromosome 3p loss of heterozygosity was not detected, and no VHL mutations were identified. These findings suggest that mutations in the TSC1 and TSC2 genes lead to clear cell renal carcinogenesis via an alternate pathway not involving VHL mutations.

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Section: Discussionmentioning

confidence: 99%

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

et al. 2002

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“…Road to treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling W van Veelen et al catalytic domains of its own but merely functions by preventing ubiquitin-mediated degradation of TSC2, thereby stabilizing intracellular TSC2 expression levels to maintain TSC2 activity (Benvenuto et al, 2000;Chong-Kopera et al, 2006). Regulation of the TSC1:TSC2 complex is mainly achieved by phosphorylation.…”

Section: Regulation Of the Tsc1:tsc2 Complexmentioning

confidence: 99%

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

et al. 2011

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The liver kinase B1 (LKB1)/adenosine mono-phosphateactivated protein kinase (AMPK)/tuberous sclerosis complex (TSC)/mammalian target of rapamycin (mTOR) complex (mTORC1) cassette constitutes a canonical signaling pathway that integrates information on the metabolic and nutrient status and translates this into regulation of cell growth. Alterations in this pathway are associated with a wide variety of cancers and hereditary hamartoma syndromes, diseases in which hyperactivation of mTORC1 has been described. Specific mTORC1 inhibitors have been developed for clinical use, and these drugs have been anticipated to provide efficient treatment for these diseases. In the present review, we provide an overview of the metabolic LKB1/AMPK/TSC/mTORC1 pathway, describe how its aberrant signaling associates with cancer development, and indicate the difficulties encountered when biochemical data are extrapolated to provide avenues for rational treatment of disease when targeting this signaling pathway. A careful examination of preclinical and clinical studies performed with rapamycin or derivatives thereof shows that although results are encouraging, we are only half way in the long and winding road to design rationale treatment targeted at the LKB1/ AMPK/TSC/mTORC1 pathway. Inherited cancer syndromes associated with this pathway such as the PeutzJeghers syndrome and TSC, provide perfect models to study the relationship between genetics and disease phenotype, and to delineate the complexities that underlie translation of biochemical and genetical information to clinical management, and thus provide important clues for devising novel rational medicine for cancerous diseases in general.

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“…There is recent evidence, based on identification of functional protein-protein interactions between hamartin and tuberin, to suggest that hamartin and tuberin comprise a cellular pathway that contributes to cell cycle passage, cell-cell interactions, and possibly cell migration. 41,42 Taken together, these reports imply that mutations in either the TSC1 or TSC2 gene likely results in a downstream cascade of common cellular events that includes changes in neurotrophin expression.…”

Section: Neurotrophin and Tuberin Expressionmentioning

confidence: 99%

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

Kyin

Yang

Baybis

et al. 2001

The American Journal of Pathology

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Neurotrophins and their receptors modulate cerebral cortical development. Tubers in the tuberous sclerosis complex (TSC) are characterized histologically by disorganized cortical cytoarchitecture and thus, we hypothesized that expression of neurotrophin mRNAs and proteins might be altered in tubers. Using in situ transcription and mRNA amplification to probe cDNA arrays, we found that neurotrophin-3 (NT3) and trkB mRNA expression were reduced whereas neurotrophin-4 (NT4) and trkC mRNA expression were increased in whole tuber sections. Alterations in mRNA abundance were defined in single microdissected dysplastic neurons (DNs) and giant cells (GCs). NT3 mRNA expression was reduced in GCs and trkB mRNA expression was reduced in DNs. NT4 mRNA expression was increased in DNs and trkC mRNA expression was increased in both DNs and GCs. In three patients, TSC2 locus mutations were confirmed and the mean tuberin mRNA expression levels was reduced across all nine cases. Consistent with these observations, NT3 mRNA expression was reduced but trkC mRNA expression was increased in vitro in human NTera2 neurons ( Tubers in the tuberous sclerosis complex (TSC) are developmental abnormalities of cerebral cortical cytoarchitecture that are associated clinically with epilepsy. [1][2][3] Electrocorticography has shown that tubers are epileptogenic and seizures in TSC patients are often medically intractable despite anticonvulsant polytherapy. 4 -6 TSC is an autosomal-dominant disorder resulting from mutations in one of two genes, TSC1 or TSC2 7,8 although the mechanism by which mutations in either TSC gene leads to tuber formation is unknown. Disorganized cortical lamination and aberrant cellular morphology are important histological features of tubers. Large dysplastic neurons (DNs) and giant cells (GCs) are prominent cell types in tubers. 9 DNs and GCs share select morphological features including cytomegaly, the extension of aberrant processes often of unclear identity, ie, axons versus dendrites, and the expression of neural protein markers such as neurofilament and ␣-internexin. 1,9,10 The TSC2 knockout mouse 11 and the Eker rat strain 12 do not fully model human brain pathology in TSC, and thus, analysis of human tuber specimens provides the only direct avenue to study the mechanisms of tuber formation. One strategy to investigate the molecular pathogenesis of cytoarchitectural disorganization in tubers is to evaluate the expression of candidate genes and proteins in human tuber specimens that are relevant to cortical development. 10 Neurotrophins and their cognate receptors comprise a family of proteins that mediate proliferation, differentiation, migration, and process outgrowth during cortical development, 13,14 and thus, are ideal candidate molecules to investigate in tubers. Brainderived neurotrophic factor (BDNF), nerve growth factor (NGF), neurotrophin 3 (NT3), and neurotrophin 4 (NT4) exert their effects on neurons by binding selectively to a family of neuronal cell membrane receptors, trks A to C. 13,14 NGF signals...

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The tuberous sclerosis-1 (TSC1) gene product hamartin suppresses cell growth and augments the expression of the TSC2 product tuberin by inhibiting its ubiquitination

Cited by 235 publications

References 38 publications

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

Mutational Analysis of the von Hippel Lindau Gene in Clear Cell Renal Carcinomas from Tuberous Sclerosis Complex Patients

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

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