Disease relevance of Tsc1

• Liver hemangiomas were more common, more severe and caused higher mortality in female than in male Tsc1 heterozygotes [1].
• Tsc1 heterozygotes develop kidney cystadenomas and liver hemangiomas at high frequency, but the incidence of kidney tumors is somewhat lower than in Tsc2 heterozygote mice [1].
• Loss of tuberous sclerosis complex 1 (Tsc1) expression results in increased Rheb/S6K pathway signaling important for astrocyte cell size regulation [2].
• Hyperphosphorylation of S6 is also seen in kidney tumors in the heterozygote mice, suggesting that inhibition of this pathway may have benefit in control of TSC hamartomas [1].
• A mouse model of cardiac rhabdomyoma generated by loss of Tsc1 in ventricular myocytes [3].

Psychiatry related information on Tsc1

• Mutations in either TSC1 or TSC2 cause tuberous sclerosis complex, an autosomal dominant disorder characterized by seizures, mental retardation, and benign tumors of the skin, brain, heart, and kidneys [4].

High impact information on Tsc1

• TSC tumorigenesis is not always accompanied by loss of heterozygosity (LOH) [5].
• Tuberous sclerosis (TSC) is an autosomal dominant genetic disorder in which benign hamartomas develop in multiple organs, caused by mutations in either TSC1 or TSC2 [6].
• We found that FIP200 knockout (KO) embryos show reduced S6 kinase activation and cell size as a result of increased tuberous sclerosis complex function [7].
• Finally, Tsc1(-/-) mouse embryonic fibroblasts (MEFs) have increased number of centrosomes and increased DNA content, compared to Tsc1(+/+) cells [8].
• RNAi inhibition of Plk1 in Tsc1(-/-) MEFs failed to rescue the increased centrosome number phenotype [8].

Chemical compound and disease context of Tsc1

• Similarly, an increased frequency and severity of liver hemangiomas was seen in Tsc1+/- males treated with estrogen [9].
• In contrast, tamoxifen treatment for 9 months significantly reduced the frequency and severity of hemangiomas in Tsc1+/- female mice [9].
• Impaired glial glutamate transport in a mouse tuberous sclerosis epilepsy model [10].
• Benign hamartomas develop in multiple organs, believed to be caused by somatic mutation in addition to germ line mutation to cause loss of both alleles of either the TSC1 or TSC2 tumor suppressor gene, with resultant dysregulated growth due to loss of hamartin or tuberin function, respectively [11].
• We identified two exon traps encoding netrin-like sequences during the assembly of a transcriptional map for the genomic interval surrounding the polycystic kidney disease type 1 and tuberous sclerosis type 2 genes [12].

Biological context of Tsc1

• A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells [1].
• In an effort to model astrocyte dysfunction in TSC, we generated mice lacking Tsc1 (hamartin) expression in astrocytes and demonstrated that Tsc1-null astrocytes exhibit abnormalities in contact inhibition growth arrest [2].
• Induction of renal tumorigenesis with elevated levels of somatic loss of heterozygosity in Tsc1+/- mice on a Blm-deficient background [13].
• Increased signal transducers and activators of transcription (STAT) 1 expression and phosphorylation at Ser 727 and increased pSTAT3 Tyr705 levels also are seen in Tsc1 null and Tsc2 null cells and in tumors [14].
• Here, we investigated whether the Blm(m3/m3) genotype could induce tumorigenesis in extracolonic tissues in tuberous sclerosis 1-deficient (Tsc1+/-) mice that are predisposed to renal cystadenomas and carcinomas [13].

Anatomical context of Tsc1

• Tsc1- and Tsc2-null cells exhibit abnormal caveolin-1 localization that is accompanied by disorganized microtubules in the subcortical region [15].
• In this report, we demonstrate that mice heterozygous for a targeted defect in either the Tsc1 or Tsc2 genes(Tsc1+/- and Tsc2+/- mice) exhibit a 1.5-fold increase in the number of astrocytes in vivo [16].
• We found that vascular endothelial growth factor (VEGF) is secreted by Tsc1- or Tsc2-null fibroblasts at high levels compared with wild-type cells [17].
• In an effort to model TSC-associated central nervous system abnormalities in mice, we generated two independent lines of astrocyte-specific Tsc1 conditional knockout mice by using the Cre-LoxP system [18].
• Tsc1-null mice show significant increases in astrocyte numbers throughout the brain by 3 weeks of age and abnormal neuronal organization in the hippocampus between 3 and 5 weeks [18].

Associations of Tsc1 with chemical compounds

• In addition, estrogen treatment significantly increased serum vascular endothelial growth factor levels in Tsc1+/- mice, whereas tamoxifen reduced vascular endothelial growth factor levels [9].
• Tsc1 Haploinsufficiency without Mammalian Target of Rapamycin Activation Is Sufficient for Renal Cyst Formation in Tsc1+/- Mice [19].
• Taken together, these findings support a model in which arginine uptake is regulated through tsc1+, tsc2+, and rhb1+ in S. pombe and also suggest a role for the Tsc1 and Tsc2 proteins in amino acid biosynthesis and sensing [4].
• Here, we report that glutamate transporter expression and function is impaired in Tsc1 cKO astrocytes [10].
• RESULTS: Human TS-related neoplasms demonstrate high-level expression of activated MAP kinase, as does a tumor arising in a mouse heterozygous for tuberin [20].

Other interactions 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 [15].
• Efficacy of a rapamycin analog (CCI-779) and IFN-gamma in tuberous sclerosis mouse models [21].
• Collectively, our results demonstrate that astrocyte-specific disruption of Tsc1 in mice provides a context-dependent growth advantage for astrocytes that results in abnormalities in neuronal organization and epilepsy [18].

Analytical, diagnostic and therapeutic context of Tsc1

• We developed a murine model of Tsc1 disease by gene targeting [1].
• Relevant animal models, including conventional and conditional knockout mice, are valuable tools for studying the normal functions of tuberin and hamartin and how disruption of their expression gives rise to the variety of clinical features that characterize tuberous sclerosis complex [22].
• Northern blot surveys demonstrated widespread TSC2 expression which was subject to developmental regulation in a tissue-specific manner [23].

References