Elizabeth Petri Henske, MD
Photo: Elizabeth P. Henske



Elected 2005
The Henske laboratory focuses on the renal and pulmonary manifestations of tuberous sclerosis complex (TSC). In the lung, young women with TSC can develop lymphangiomyomatosis (LAM), which is a diffuse smooth muscle cell infiltrate accompanied by cystic lung degeneration. We found that somatic mutations in the TSC2 gene cause a sporadic form of LAM. Genetic data indicate that LAM results from a very unusual disease mechanism: metastasis of histologically benign smooth muscle cells. In the kidney, most TSC patients develop angiomyolipomas, which are composed of abnormal blood vessels, smooth muscle cells, and fat cells. We have found that all three components are derived from the same precursor cell, suggesting that tuberin regulates the differentiation of renal mesenchymal cells. Because of the "benign metastasis" model for LAM and the differentiation plasticity in angiomyolipomas, we are currently focusing on the roles of the TSC proteins in cellular pathways regulating growth, differentiation, and metastasis. We found that tuberin, the TSC2 gene product, activates B-Raf kinase via Rheb, the Ras homologue that is the target of tuberin's GTPase activating domain. We have also found that hamartin, the TSC1 gene product, regulates the activity of tuberin in a cell cycle dependent manner. Finally, we have found that Schizosaccharomyces pombe lacking tsc1 or tsc2 have decreased arginine uptake, decreased expression of three amino acid permeases, and low intracellular levels of four members of the arginine biosynthesis pathway, suggesting a role for the TSC proteins in amino acid biosynthesis and sensing.