Disease relevance of Tsc2

• Eker leiomyomas exhibited a 50% incidence of loss of the wild-type Tsc2 allele and an almost uniform loss of protein expression, implicating loss of function of the Tsc2 gene in these tumors [1].
• Exogenously expressed caveolin-1-GFP and vesicular stomatitis virus G protein, VSVG-GFP in the Tsc2-/- cells failed to be transported to the plasma membrane and were retained in distinct post-Golgi vesicles [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].
• The goals of this study were to characterize the apoptotic response of a tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene-null cell line, to establish valid biochemical events that can be used as apoptosis markers, and to determine how these events correlate with apoptosis-specific morphologic changes [5].

High impact information on Tsc2

• 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 [6].
• In tuberin-deficient cells, intracellular trafficking of polycystin-1 was disrupted, resulting in sequestration of polycystin-1 within the Golgi and reexpression of Tsc2 restored correct polycystin-1 membrane localization [7].
• Loss of function of the normal Tsc-2 allele remained the rate-limiting event for tumorigenesis; however, tumors that developed in exposed animals displayed an enhanced proliferative response to steroid hormones relative to tumors that developed in unexposed animals [8].
• The tuberous sclerosis complex gene-2 (TSC2) on chromosome 16 encodes the tumor suppressor protein tuberin [9].
• Predisposition to renal carcinoma in the Eker rat is determined by germ-line mutation of the tuberous sclerosis 2 (TSC2) gene [10].

Chemical compound and disease context of Tsc2

• Uterine myometria and spontaneous leiomyomas from the Eker rat, which carries a germ-line mutation in the tuberous sclerosis complex-2 (Tsc2) tumor suppressor gene, were analyzed for genetic defects in and expression of the Tsc2 and HMGA proteins [1].
• The gene expression profiles of the Tsc2 heterozygous mutant and wild-type animals highlights new pathways for investigation that may be associated with the tumorigenic activity of tuberin loss and correlate with the enhanced susceptibility of the Tsc2 mutant animal's tendency to develop renal cell carcinoma [11].

Biological context of Tsc2

• The presence of mislocalized proteins in Tsc2-/- cells may contribute to the abnormal signaling and cellular phenotype of tuberous sclerosis [2].
• In this study, we characterized the rat Tsc2 cDNA and found that it is highly homologous with the human gene, including a conserved rap1GAP catalytic domain [12].
• Sequence analysis of independent rat clones from a kidney cDNA library revealed distinct but related variants of the Tsc2 transcripts stemming from alternative splicing involving two noncontiguous exons within the translated region [12].
• A mutant of tuberin from a patient missense mutation of TSC2 was also highly ubiquitinated, and was unable to stabilize hamartin [13].
• Here, rats carrying a germline mutation of the gene Tsc2 were found to develop variable size and number of renal tumors [14].

Anatomical context of Tsc2

• Tsc1- and Tsc2-null cells exhibit abnormal caveolin-1 localization that is accompanied by disorganized microtubules in the subcortical region [15].
• Correspondingly, there was a paucity of caveolae at the plasma membrane of Tsc2-/- cells [2].
• We previously characterized the apoptotic response of a Tsc2-null renal tumor cell line (ERC-18) to the tumor promoter okadaic acid (OKA) [16].
• A new Western blotting method using polymer immunocomplexes: detection of Tsc1 and Tsc2 expression in various cultured cell lines [17].
• We examined the pattern and frequency of LOH at the predisposing locus in 77 primary tumors and cell lines to gain an understanding of the role of Tsc2 allelic loss in the pathogenesis of Eker-derived tumors [18].

Associations of Tsc2 with chemical compounds

• Reexpression of Tsc2 in tuberin-negative cells decreased ERK activity, consistent with the growth-suppressive effects of this tumor suppressor gene [19].
• Tsc2 expression increased the susceptibility of ERC-18 cells to apoptosis induced by OKA and the phosphatidylinositol-3' kinase inhibitor, LY294002 [16].
• The function of the TSC2/Tsc2 gene product (called "tuberine" in the human case) is not yet understood, although it contains a short amino acid sequence homologous to the ras family GTPase-activating proteins (GAP3) [20].
• In cells lacking tuberin, most of the endogenous caveolin-1 was displaced from the plasma membrane to a Brefeldin-A-sensitive, post-Golgi compartment distinct from the endosome and lysosome [2].
• To further characterize the microsomal pool of tuberin, we found that it cofractionated with caveolin-1 in a low-density, Triton X-100-resistant fraction (i.e., lipid rafts) and regulated its localization [2].

Physical interactions of Tsc2

• Co-expression of tuberin stabilized hamartin, which is weakly ubiquitinated, in transiently transfected cells [13].

Regulatory relationships of Tsc2

• Epidermal growth factor can similarly induce tuberin phosphorylation and degradation via a PI3K/Akt pathway in PC-12 cells, but these responses were insensitive to pertussis toxin treatment [21].

Other interactions of Tsc2

• Retention of membrane-localized beta-catenin in cells lacking functional polycystin-1 and tuberin [22].
• EKT2 cells lacking tuberin because of inactivation of the Tsc2 gene fail to localize polycystin-1 and E-cadherin appropriately to these junctions [22].
• These results indicate that the OKA-induced, caspase-independent detachment previously observed in ERC-18 cells is Tsc2-dependent, and may support an additional role for the Tsc2 in regulating cell adhesion [16].
• Tuberin is a component of lipid rafts and mediates caveolin-1 localization: role of TSC2 in post-Golgi transport [2].
• Platelet-derived growth factor-induced p42/44 mitogen-activated protein kinase activation and cellular growth is mediated by reactive oxygen species in the absence of TSC2/tuberin [23].

Analytical, diagnostic and therapeutic context of Tsc2

• A combination of laser capture microdissection and semi-nested polymerase chain reaction demonstrated the presence of the wild-type Tsc2 allele in the cytomegalic neurons isolated individually [24].
• Immunohistochemistry also detected positive tuberin immunoreactivity in many of these giant neurons [24].
• The Eker rat is an animal model of tuberous sclerosis caused by a mutation in the Tsc2 gene encoding a tumor suppressor protein, tuberin [24].
• We tested the hypothesis that estrogen treatment or ovariectomy of rats modulates renal tumor development using tuberous sclerosis 2 (Tsc2) heterozygous mutant (Eker) rats in which a germline mutation predisposes the animals to renal cell tumor development [25].
• Indirect immunofluorescence of tuberin in various cultured cell lines revealed a punctate, mostly perinuclear staining pattern [26].

References