TSC1 and TSC2 are two genes involved in the autosomal dominant disorder of tuberous sclerosis complex (TSC). Its incidence has been reported as 1 in 6,000 live births and many suffer complications resulting in premature deaths. The most debilitating effects of TSC are its central nervous system and renal manifestations, including epilepsy, mental retardation, hemorrhage and renal cancer. Treatments for these conditions are both difficult and limited often requiring hospitalization and institutionalization. With the genetic identification of the two genes, TSC1 and TSC2, responsible for this disorder, efforts are now underway to elucidate their biochemical and cellular mechanisms. Research over the last few years have yielded several clues to their function but specific pathways under the influence of hamartin and tuberin, and those regulating them remain largely unknown. When viewed under the microscope, lesions associated with TSC share several common abnormalities in terms of cell number, cell shape and size, and their geographic location. These observations point to underlying defects in cell cycle control, cell growth, cell differentiation, and cell migration. The objective of this study is to elucidate the function of TSC 1 and TSC2 by focusing on their role in protein sorting, transport and localization. It has been demonstrated that tuberin and hamartin, acting as a functional complex, affect the intracellular distribution of certain proteins. This led to the hypothesis that these genes play a critical role in regulating protein trafficking.
The specific aims of the proposal are focused on defining the subcellular localization of the mis-targeted proteins, the identification of the spectrum of proteins whose localization are affected by TSC2, the biosynthetic and sorting pathway(s) involved, the functional consequences of abnormal protein trafficking with emphasis on cell proliferation and adhesion, and the underlying mechanism. The results of these experiments will enable us to better understand the pathogenesis of tumor development and their clinical sequelae in tuberous sclerosis and related disorders.
Showing the most recent 10 out of 15 publications
