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

Abstract

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.

Differential Cellular Expression of Neurotrophins in Cortical Tubers of the Tuberous Sclerosis Complex

“…In addition, previous studies in human neuroblastoma cell lines have demonstrated that tuberin AS-constructs reduce tuberin expression and alter cell cycle dynamics. 39 The AS-constructs did not alter cellular morphology in the NT2N, yet tuberin mRNA and protein expression was diminished by Ͼ60% and a similar reduction in tuberin expression observed in the C6 glioma cell line supported the validity of the AS-construct effects on tuberin expression. The apparently normal morphology of AS-transfected NT2N cells may have reflected the presence of enough functional tuberin to maintain cellular cytoarchitecture or may require more rigorous evaluation of subtle structural alterations.…”

The tumor suppressor tuberin regulates mitotic onset through the cellular localization of cyclin B1

“…6,7 Loss of tuberin expression has also been shown to lead to the cytoplasmic mislocalization and functional inactivation of the cyclindependent kinase (CDK) inhibitor p27. 7,8 While current work on TS is primarily focused on the regulation of G 1 /S phases of the tuberous sclerosis is a multi-organ disorder characterized by the formation of benign tumors, called hamartomas, which affects more than 1 million people worldwide. the syndrome is initiated by a mutation in one of two tumor suppressor genes, tSC1 or tSC2, that encode for the proteins hamartin and tuberin, respectively.…”

Akt regulates nuclear/cytoplasmic localization of tuberin

“…Hamartin stabilizes tuberin by inhibiting its interaction with the HERC1 ubiquitin ligase (Chong-Kopera et al, 2006). Tuberin has been implicated in the regulation of different cellular functions, such as endocytosis (Xiao et al, 1997), transcription (Henry et al, 1998) or neuronal differentiation (Soucek et al, 1998a). Tuberin and hamartin also regulate cell cycle progression.…”