A de novo frame-shift mutation in the tuberin gene

Kumar, Archana Vijaya; Wolpert, Chantelle M.; Kandt, Raymond S.; Segal, Jair; Pufky, John; Roses, A.D.; Pericak‐Vance, Margaret A.; Gilbert, JR

doi:10.1093/hmg/4.8.1471

Cited by 32 publications

(13 citation statements)

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“…Such a scenario may underly the development of inappropriate growths (tubers/hamartomas) in the central nervous system, which is the hallmark of TSC. Mutations in the TSC2 gene have been described in patients with TSC (Kumar et al, 1995;Wilson et al, 1996) and loss of heterozygosity at the TSC2 locus has been demonstrated in TSC patient lesions (Green et al, 1994;Henske et al, 1995;Carbonara et al, 1996). It was recently demonstrated that neurons in cortical tubers of TSC patients express several mRNAs and proteins, which are characteristic of embryonic neuroepithelial precursor cells (Crino et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the TSC2 gene have been described in patients with TSC (Kumar et al, 1995;Wilson et al, 1996) and loss of heterozygosity at the TSC2 locus has been demonstrated in TSC patient lesions, as well as in sporadic tumours of non-TSC patients (Green et al, 1994;Henske et al, 1995;Carbonara et al, 1996). The TSC2-encoded protein, designated tuberin, functions as a GTPase accelerating protein (GAP) for the small molecular weight GTPases Rap1a and Rab5 (Wienecke et al, 1995Xiao et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 1998

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“…Linkage studies in families with TSC show that about 50% are associated with a mutant TSC2 gene, located on chromosome 16, while an as yet unidentified gene (TSC1), which maps to chromosome 9, is implicated in the remainder (4 -8). Mutations in the TSC2 gene have been described in patients with TSC (9,10), and loss of heterozygosity at the TSC2 locus has been demonstrated in TSC patient lesions as well as in sporadic tumors of non-TSC patients (11)(12)(13). The TSC2-encoded protein, designated tuberin, contains a region of homology to the GTPase-accelerating protein (GAP) for the small molecular weight GTPase Rap1, which is a member of the superfamily of Ras-related proteins (4).…”

Section: Tuberous Sclerosis (Tsc)mentioning

confidence: 99%

Role of the Tuberous Sclerosis Gene-2 Product in Cell Cycle Control

Soucek

Pusch

Wienecke

et al. 1997

Journal of Biological Chemistry

179

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“…Mutations in the TSC2 gene have been described in patients with TSC (10,11), and loss of heterozygosity at the TSC2 locus has been demonstrated in TSC patient lesions, as well as in sporadic tumors of non-TSC patients (12)(13)(14). The TSC2-encoded protein, designated tuberin, functions as a GTPase accelerating protein for the small molecular weight GTPases Rap1a and Rab5 (15)(16)(17).…”

mentioning

confidence: 99%

“…In addition, early passages (10)(11)(12)(13)(14) of primary embryonic fibroblasts derived from TSC2-positive (EEF-TSC2ϩ͞ϩ) and TSC2-negative (EEF-TSC2Ϫ͞Ϫ) Eker rats were used in this study. SKNSH human neuroblastoma cells were obtained from the American Type Culture Collection (ATCC HB11), and Rat1 and Rat1-MycER cells were kindly provided by M. Eilers (Marburg, Germany).…”

mentioning

confidence: 99%

Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2

Soucek

Yeung

Hengstschläger

1998

Proc. Natl. Acad. Sci. U.S.A.

162

117

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Tuberous sclerosis is an autosomal dominant disorder characterized by the development of aberrant growths in many tissues and organs. Linkage analysis revealed two disease-determining genes on chromosome 9 and chromosome 16. The tuberous sclerosis complex gene-2 (TSC2) on chromosome 16 encodes the tumor suppressor protein tuberin. We have shown earlier that loss of TSC2 is sufficient to induce quiescent cells to enter the cell cycle. Here we show that TSC2-negative fibroblasts exhibit a shortened G 1 phase. Although the expression of cyclin E, cyclin A, p21, or Cdc25A is unaffected, TSC2-negative cells express much lower amounts of the cyclin-dependent kinase (CDK) inhibitor p27 because of decreased protein stability. In TSC2 mutant cells the amount of p27 bound to CDK2 is diminished, accompanied with elevated kinase activity. Ectopic expression studies revealed that the aforementioned effects can be reverted by transfecting TSC2 in TSC2-negative cells. High ectopic levels of p27 have cell cycle inhibitory effects in TSC2-positive cells but not in TSC2-negative counterparts, although the latter still depend on CDK2 activity. Loss of TSC2 induces soft agar growth of fibroblasts, a process that cannot be inhibited by high levels of p27. Both phenotypes of TSC2-negative cells, their resistance to the activity of ectopic p27, and the instability of endogenous p27, could be explained by our observation that the nucleoprotein p27 is mislocated into the cytoplasm upon loss of TSC2. These findings provide insights into the molecular mechanism of how loss of TSC2 induces cell cycle entry and allow a better understanding of its tumor suppressor function.

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A de novo frame-shift mutation in the tuberin gene

Cited by 32 publications

References 0 publications

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

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

Role of the Tuberous Sclerosis Gene-2 Product in Cell Cycle Control

Inactivation of the cyclin-dependent kinase inhibitor p27 upon loss of the tuberous sclerosis complex gene-2

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