A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer

Kobayashi, Toshiyuki; Hirayama, Youko; Kobayashi, Etsuko; Kubo, Yoshiaki; Hino, Okio

doi:10.1038/ng0195-70

Cited by 279 publications

(177 citation statements)

References 17 publications

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“…The Eker rat, which carries a germline mutation in the rat TSC2 homologue, develops renal cysts and carcinomas with an autosomal-dominant pattern of inheritance (27,28). Two groups have developed mice with targeted inactivation of TSC2 (29,30).…”

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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“…In other organs such as the adrenals, brain, pituitary, small and large intestine, stomach, testis, and retina, the distributions of the two proteins overlapped, but were not identical. Tsc1 and Tsc2 are the genes responsible for human TSC and renal carcinogenesis in rodents (European chromosome 16 tuberous sclerosis consortium, 1993; Kobayashi et al, 1995Kobayashi et al, , 1999Onda et al, 1999;van Slegtenhorst et al, 1997), and binding between two proteins has been reported as the possible cooperative function (Plank et al, 1998;van Slegtenhorst et al, 1998). In terms of cell type specificity, the overlapped, but not identical expression profile between Tsc1 and Tsc2 suggest that Tsc1 protein does not always associate with Tsc2 in all organs and tissues.…”

Section: Discussionmentioning

confidence: 99%

Distribution of Tsc1 Protein Detected by Immunohistochemistry in Various Normal Rat Tissues and the Renal Carcinomas of Eker Rat: Detection of Limited Colocalization with Tsc1 and Tsc2 Gene Products In Vivo

Fukuda

Kobayashi

Momose

et al. 2000

Laboratory Investigation

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SUMMARY:We and others previously demonstrated that hereditary mutation and a subsequent second hit in the rat homolog of tuberous sclerosis gene (Tsc2) are responsible for Eker renal carcinomas (RC). In humans, alteration in the TSC2 gene is known to cause the tuberous sclerosis complex (TSC) that results in hamartomatous lesions in multiple organs, but the function of TSC2 is not fully understood. In recent years, a second gene (TSC1) responsible for human TSC has been cloned, and binding between TSC1 and TSC2 proteins was reported. In this study, to clarify associations between Tsc proteins in vivo, the expression of Tsc1 protein was detected by immunohistochemistry, and compared with Tsc2 expression. Tsc1 protein was expressed in the nervous system and in many endocrine tissues, including pancreatic islets, the parathyroids, testis, and ovary. Tsc1 was also detected in the many epithelial tissues of organs, such as kidney, uterus, small and large intestine, and liver. Our results indicate overlapping, but not identical, organ distributions of Tsc1 and Tsc2 proteins. At the intracellular distribution, double fluorescent immunolabeling allowed the determination that only a partial portion of Tsc1 signals overlapped with Tsc2 in some organs. These results suggest the existence of co-localizing and independent forms of Tsc proteins in endogenous expressions. Additionally, relatively high expression of Tsc1 protein was detected in RC in the Tsc2 mutant (Eker) rat. (Lab Invest 2000, 80:1347-1359.

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“…The Eker mutation is a germline insertion in the rat homologue of the human TSC2 gene, resulting in premature truncation of TSC2 (Yeung et al, 1994;Kobayashi et al, 1995;Xiao et al, 1995). Heterozygous carriers are characterized by the onset of renal tumours, sometimes associated with other neoplasia and the susceptibility of these rats to carcinogens is increased (Walker et al, 1992;Hino et al, 1993).…”

Section: Introductionmentioning

confidence: 99%

A role of the tuberous sclerosis gene-2 product during neuronal differentiation

et al. 1998

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Tuberous sclerosis is an autosomal dominant disorder. Besides the development of benign growths (hamartomas) in di erent tissues, one hallmark of this disease is the presence of highly epileptogenic dysplastic lesions in the cerebral cortex (tubers) composed of abnormal shaped neurones. Patients often show evidence of severe mental retardation. Linkage analysis revealed two diseasedetermining genes on chromosome 9 and chromosome 16. The TSC2 gene on chromosome 16 encodes a 1784-amino acid putative tumour suppressor protein, tuberin, that functions as a GTPase-activating protein. Here we show that tuberin expression is upregulated upon induction of neuronal di erentiation in the neuroblastoma cell lines SK-N-SH and LAN-1. This upregulation occurs at post-transcriptional level and is independent of the proliferation status. TSC2 expression is una ected during di erentiation of C2C12 myoblasts into myotubes and of F9 embryonal carcinoma cells into cells resembling parietal endoderm. Antisense inhibition of tuberin expression in SK-N-SH or LAN-1 cells inhibits neuronal di erentiation, but does not a ect the di erentiation of F9 cells. Ectopic overexpression of TSC2 not only reverts the antisense-associated phenotype but furthermore accelerates the neuronal di erentiation process. Our data show for the ®rst time that tuberin plays a critical role in neuronal di erentiation. Such role is consistent with the phenotype of tuberous sclerosis patients, who inherit one defective TSC2 allele, and frequently lose the remaining normal allele in many of the tubers/hamartomas which develop in the central nervous system of these patients.

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A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer

Cited by 279 publications

References 17 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

Distribution of Tsc1 Protein Detected by Immunohistochemistry in Various Normal Rat Tissues and the Renal Carcinomas of Eker Rat: Detection of Limited Colocalization with Tsc1 and Tsc2 Gene Products In Vivo

A role of the tuberous sclerosis gene-2 product during neuronal differentiation

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