Disease relevance of Tsc1

• Mutations of the TSC2 gene lead to the development of hamartomas in tuberous sclerosis complex [1].
• Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in the TSC1 or TSC2 genes, which encode hamartin and tuberin, respectively [2].
• Alterations in the rat tuberous sclerosis gene (Tsc2) cause renal cell carcinomas (RCCs) with complete penetrance [3].
• Eker rats develop dominantly inherited renal carcinomas (RCs), with hereditary mutation, and following somatic mutation (Knudson's second hit) at tuberous sclerosis gene (Tsc2) [4].
• Individuals at high risk for this disease include persons with end-stage renal disease, those with hereditary predispositions such as von Hippel-Lindau syndrome (VHL) or tuberous sclerosis (TSC), and individuals with significant environment exposures such as smoking or analgesic abuse [5].

Psychiatry related information on Tsc1

• Tuberous sclerosis (TS) is an autosomal dominant disorder in which affected individuals manifest mental retardation, seizures, and a variety of benign and malignant tumors [6].

High impact information on Tsc1

• The phenotype of tuberous sclerosis in humans differs from that of the Eker rat, except for the occurrence of renal tumours [7].
• We have previously established a new conserved linkage group on rat chromosome 10q and human chromosome 16p13.3, and shown that the Eker mutation is tightly linked to the tuberous sclerosis (Tsc2) gene [7].
• We now describe a germline mutation in the gene encoding Tsc2 caused by the insertion of an approximately 5 kilobase DNA fragment in the Eker rat, resulting in aberrant RNA expression from the mutant allele [7].
• Furthermore, loss of a single copy of the Tsc1 gene was sufficient to perturb dendritic spine structure [8].
• Heterozygous Tsc1 mutant (Tsc1(+/-)) mice developed renal and extra-renal tumors such as hepatic hemangiomas [9].

Biological context of Tsc1

• Recent studies have identified TSC1 and TSC2, two tumor suppressor genes involved in tuberous sclerosis complex, as regulators of the mammalian target of rapamycin (mTOR) pathway [10].
• A mutant of tuberin from a patient missense mutation of TSC2 was also highly ubiquitinated, and was unable to stabilize hamartin [11].
• The presence of mislocalized proteins in Tsc2-/- cells may contribute to the abnormal signaling and cellular phenotype of tuberous sclerosis [1].
• Tuberin and hamartin inhibit signaling by the mammalian target of rapamycin (mTOR) but there are limited studies of their involvement in other pathways controlling cell growth [2].
• Absence of allelic loss in cytomegalic neurons of cortical tuber in the Eker rat model of tuberous sclerosis [12].

Anatomical context of Tsc1

• Tsc1- and Tsc2-null cells exhibit abnormal caveolin-1 localization that is accompanied by disorganized microtubules in the subcortical region [10].
• A new Western blotting method using polymer immunocomplexes: detection of Tsc1 and Tsc2 expression in various cultured cell lines [13].
• Tsc1 was also detected in the many epithelial tissues of organs, such as kidney, uterus, small and large intestine, and liver [14].
• Tsc1 protein was expressed in the nervous system and in many endocrine tissues, including pancreatic islets, the parathyroids, testis, and ovary [14].
• In the Eker rat, a germ-line mutation in the homologue of the human tuberous sclerosis gene (Tsc2) causes renal cell carcinomas (RCs) with a complete penetrance in all heterozygotes [15].

Associations of Tsc1 with chemical compounds

• Tuberin could function as a tumor suppressor without binding to hamartin [16].
• Spatial memory formation and memory-enhancing effect of glucose involves activation of the tuberous sclerosis complex-Mammalian target of rapamycin pathway [17].
• Recent genetic and biochemical studies have identified a role for the tuberous sclerosis gene products in phosphoinositide 3-kinase signaling [18].
• Rescue from embryonic lethality of mutant homozygotes (Eker/Eker) and suppression of N-ethyl-N-nitrosourea-induced renal carcinogenesis in heterozygotes (Eker/+) were both observed, defining the germ-line Tsc2 mutation in the Eker rat as embryonal lethal and tumor predisposing mutation [19].
• N-ethyl-N-hydroxyethylnitrosamine (EHEN)- and diethylnitrosamine (DEN)-induced non-Eker rat primary RCs were subjected to polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) analysis using specific primers covering all exons of the Tsc2 gene (41 coding exons and 1 non-coding exon) [20].

Physical interactions of Tsc1

• Co-expression of tuberin stabilized hamartin, which is weakly ubiquitinated, in transiently transfected cells [11].

Other interactions of Tsc1

• Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2 [21].

Analytical, diagnostic and therapeutic context of Tsc1

• The Eker rat is an animal model of tuberous sclerosis caused by a mutation in the Tsc2 gene encoding a tumor suppressor protein, tuberin [12].
• Finally, we show that at endogenous expression levels, hamartin has a punctate pattern of immunofluorescence in the cytoplasm [22].
• Primary cell cultures of oligodendroglioma, meningioma, and glioblastoma multiforme origin were also found to express hamartin [23].
• Using co-immunoprecipitation, we have also confirmed the physical interaction of tuberin and hamartin in a diverse range of human and rat cell types [23].
• Distribution of Tsc2 protein in various normal rat tissues and renal tumours of Tsc2 mutant (Eker) rat detected by immunohistochemistry [24].

References