Disease relevance of TSC1

• Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome caused by mutations in TSC1 and TSC2 [1].
• Tuberous sclerosis is an autosomal dominant hereditary disease caused by mutations in either the TSC1 or the TSC2 tumor suppressor gene [2].
• Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation [3].
• Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas [4].
• This high incidence of mTOR signaling pathway activation suggests that treatment with mTOR inhibitors, such as Rapamycin, may benefit patients with angiomyolipomas independent of the detection of TSC1/TSC2 loss of heterozygosity [5].

Psychiatry related information on TSC1

• Mental retardation was significantly less frequent among carriers of TSC1 than TSC2 mutations (odds ratio 5.54 for sporadic cases only, 6.78 +/- 1.54 when a single randomly selected patient per multigeneration family was also included) [6].
• Recent data suggest that functional inactivation of TSC proteins might also be involved in the development of other diseases not associated with TSC, such as sporadic bladder cancer, breast cancer, ovarian carcinoma, gall bladder carcinoma, non-small-cell carcinoma of the lung, and Alzheimer's disease [7].
• Tuberous sclerosis (TSC) is an autosomal dominant disorder characterised by tumour-like malformations (hamartomas) of the brain, skin, and other organs, often associated with seizures and learning disability [8].
• Thus, the incidence of autistic disorder in tuberous sclerosis complex is 16% [9].
• The molecular defects responsible for Huntington's disease, the spinocerebellar degenerations, myotonic muscular dystrophy, neurofibromatosis, and tuberous sclerosis, among other major dominant inherited diseases of the nervous system, will be identified using the new techniques of molecular genetics [10].

High impact information on TSC1

• Mutation in the TSC2 tumor suppressor causes tuberous sclerosis complex, a disease characterized by hamartoma formation in multiple tissues [11].
• High levels of dysregulated mTOR activity are associated with several hamartoma syndromes, including tuberous sclerosis complex, the PTEN-related hamartoma syndromes and Peutz-Jeghers syndrome [12].
• Mosaicism in tuberous sclerosis as a potential cause of the failure of molecular diagnosis [13].
• Images in clinical medicine. Ash-leaf spots in tuberous sclerosis [14].
• Renal cysts are often found in TSC, but a specific renal phenotype, distinguished by the severity and infantile presentation of the cystic changes, is seen in a small proportion of cases [15].

Chemical compound and disease context of TSC1

• Further characterization of the roles of hamartin and tuberin will provide potential therapeutic avenues to treat seizures, mental retardation, and tumor growth in TSC [16].
• Since the MMPH was observed in a male and did not appear to possess malignant potential, the MMPH appears to be a hamartomatous proliferation occurring in a male with tuberous sclerosis that is separate from lymphangiomyomatosis (LAM) which is related to estrogen and progesterone receptors [17].
• Lymphangioleiomyomatosis (LAM) is a rare disease that occurs primarily in women and has been linked to both estrogen-mediated signaling events and mutations associated with the tuberous sclerosis complex 2 gene product tuberin [18].
• Altogether, our results provide molecular insight into the mechanisms of mycobacteria-DC-SIGN interaction, and suggest that DC-SIGN may act as a pattern recognition receptor and discriminate between Mycobacterium species through selective recognition of the mannose caps on LAM molecules [19].
• CONCLUSIONS: These results confirm previous reports of the efficacy and safety of vigabatrin in patients with infantile spasms, particularly among those with spasms secondary to tuberous sclerosis [20].

Biological context of TSC1

• We have now comprehensively defined the TSC1 mutational spectrum in 171 sequentially ascertained, unrelated TSC patients by single strand conformation polymorphism and heteroduplex analysis of all 21 coding exons, and by assaying a restriction fragment spanning the whole locus [6].
• Molecular genetic and phenotypic analysis reveals differences between TSC1 and TSC2 associated familial and sporadic tuberous sclerosis [6].
• Inactivating mutations to either of the TSC1 and TSC2 tumour suppressor genes are responsible for the disease [21].
• The TSC1 gene product, hamartin, negatively regulates cell proliferation [2].
• Both large deletions and missense mutations were common at the TSC2 locus whereas most TSC1 mutations were small truncating lesions [6].

Anatomical context of TSC1

• IRS1 is preferentially depleted from the high-speed pellet fraction in TSC1/2-deficient mouse embryo fibroblasts or in HEK293/293T cells overexpressing Rheb [22].
• The TSC1 tumor suppressor hamartin interacts with neurofilament-L and possibly functions as a novel integrator of the neuronal cytoskeleton [23].
• CONCLUSION: TSC1 genes are aberrantly expressed in human breast cancer cell lines and breast tumour tissues and their promoters are seen to be methylated in breast tumour tissues [24].
• Here, we performed microarray analyses of the gene expression response to overexpressed TSC1 or TSC2 in HeLa cells [25].
• We used a recently described DHPLC assay allowing the efficient detection of mutations in TSC1 to analyze the DNA extracted from a chorion villus sample in order to perform a prenatal diagnosis for TSC [26].

Associations of TSC1 with chemical compounds

• Tuberin and hamartin form a complex that inhibits signaling by the mammalian target of rapamycin (mTOR), a critical nutrient sensor and regulator of cell growth and proliferation [27].
• Here, we demonstrate that endogenous hamartin is threonine-phosphorylated during nocodazole-induced G2/M arrest and during the G2/M phase of a normal cell cycle [28].
• Here we show that tuberin-hamartin heterodimers block protein kinase C (PKC)/MAPK- and phosphatidic acid-mediated signaling toward mammalian target of rapamycin-dependent targets [29].
• Additionally, either Tsc1/2 or Tor1 are required for growth on a poor nitrogen source such as proline [30].
• Mutants lacking Tsc1 or Tsc2 are highly sensitive to rapamycin under poor nitrogen conditions, suggesting that the function of Tor1 under such conditions is sensitive to rapamycin [30].

Physical interactions of TSC1

• Inactivation of the tuberous sclerosis complex-1 and -2 gene products occurs by phosphoinositide 3-kinase/Akt-dependent and -independent phosphorylation of tuberin [29].
• Tumor-promoting phorbol esters and activated Ras inactivate the tuberous sclerosis tumor suppressor complex via p90 ribosomal S6 kinase [27].
• Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta [31].
• Hamartin also binds to ezrin and other ezrin-radixin-moesin proteins, which link the cell membrane to the cytoskeleton [32].
• Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins. A molecular link of two tumor suppressor pathways [33].

Regulatory relationships of TSC1

• 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 [34].
• The TSC proteins have been implicated in the control of cell cycle by activating the cyclin-dependent kinase inhibitor p27 and in cell size regulation by inhibiting the mammalian target of rapamycin (mTOR)/p70S6K cascade [35].
• Tuberous sclerosis mutations activate mammalian target of rapamycin (mTOR) and biochemically resemble VHL alterations [36].
• The LKB1 tumor suppressor protein controls the activity of the TSC1/TSC2 tumor suppressor complex [37].
• AMT PET can provide independent complementary information regarding the localization of epileptogenic regions in tuberous sclerosis complex and enhance the confidence of patient selection for successful epilepsy surgery [38].

Other interactions of TSC1

• This study provides new insights into the cellular roles of TSC proteins and initiates a discussion of whether separable functions of these proteins might be associated with the clinical differences of TSC1- and TSC2-associated disease [39].
• Insulin activation of Rheb, a mediator of mTOR/S6K/4E-BP signaling, is inhibited by TSC1 and 2 [40].
• Together these findings suggest that MCP-1 is an important paracrine factor for TSC tumorigenesis and may be a new therapeutic target [41].
• Rheb fills a GAP between TSC and TOR [42].
• We also demonstrate that hamartin interacts with CDK1 and cyclin B1 [43].

Analytical, diagnostic and therapeutic context of TSC1

• Here, to analyze the function of the Tsc1 product, we established a line of Tsc1 (TSC1 homologue) knockout mouse by gene targeting [44].
• Using methylation specific PCR, the TSC1 promoter was found to be heavily methylated in ZR751, MDA MB 435, and BT549, but not in MCF-7 which expressed highly level of hamartin [24].
• In this study, we performed two-dimensional gel electrophoresis with subsequent mass spectrometrical identification of protein spots after overexpression of TSC1 or TSC2 [45].
• Western blot analyses confirmed the deregulation of 14-3-3 proteins upon ectopic overexpression of TSC1 and TSC2 [46].
• Investigations of TSC1 and TSC2 in a number of model organisms and cell-culture systems have provided new insights into the mechanisms through which these roles are effected [47].

References