The role of tuberin in p27 regulation

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting about 1 in 6000 individuals. It is characterized by the development of tumor-like growths, named hamartomas, in the kidneys, heart, skin and brain. The latter often cause seizures, mental retardation and a variety of developmental disorders, including autism. Two genes have been shown to be responsible for this disease: TSC1 on chromosome 9q34 encoding hamartin and TSC2 on chromosome 16p13.3 encoding tuberin. TSC patients carry a mutant TSC1 or TSC2 gene in each of their somatic cells and loss of heterozygosity has been documented in a wide variety of TSC tumors. Hamartin and tuberin form a complex, providing a tentative explanation for the similar disease phenotype in TSC patients with mutations in either of these genes. The TSC proteins have been implicated in the regulation of different cellular functions, such as transcription, neuronal differentiation, cell cycle and cell size control. Further elucidation of the molecular functions of TSC proteins may allow the development of new therapeutic strategies. Tuberin is also known to regulate nuclear localization of the cyclin-dependent kinase inhibitor p27. In this project we want to investigate the underlying molecular mechanism. Furthermore, tuberin protects p27 from Skp2- dependent protein degradation. We plan to investigate the regulation of these two effects throughout the mammalian cell cycle. Tuberins activity is activated and inactivated via phosphorylation. Phosphorylation of tuberin is mediated via the PI3K/Akt pathway, via the MAP kinase pathway and via the LKB1/AMPK pathway. In this project the question will be investigated which of these pathways regulates p27 stability and/or localization in a tuberin-dependent manner.

Tuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor gene syndrome affecting about 1 in 6000 individuals. It is characterized by the development of tumor-like growths, named hamartomas, in the kidneys, heart, skin and brain. The latter often cause seizures, mental retardation and a variety of developmental disorders, including autism. Two genes have been shown to be responsible for this disease: TSC1 on chromosome 9q34 encoding hamartin and TSC2 on chromosome 16p13.3 encoding tuberin. TSC patients carry a mutant TSC1 or TSC2 gene in each of their somatic cells and loss of heterozygosity has been documented in a wide variety of TSC tumors. Hamartin and tuberin form a complex, providing a tentative explanation for the similar disease phenotype in TSC patients with mutations in either of these genes. The TSC proteins have been implicated in the regulation of different cellular functions, such as transcription, neuronal differentiation, cell cycle and cell size control. Further elucidation of the molecular functions of TSC proteins may allow the development of new therapeutic strategies. Tuberin is also known to regulate nuclear localization of the cyclin-dependent kinase inhibitor p27. In this project we want to investigate the underlying molecular mechanism. Furthermore, tuberin protects p27 from Skp2- dependent protein degradation. We plan to investigate the regulation of these two effects throughout the mammalian cell cycle. Tuberin`s activity is activated and inactivated via phosphorylation. Phosphorylation of tuberin is mediated via the PI3K/Akt pathway, via the MAP kinase pathway and via the LKB1/AMPK pathway. In this project the question will be investigated which of these pathways regulates p27 stability and/or localization in a tuberin-dependent manner.