Cancer genetics, renal carcinoma, tuberous sclerosis complex, LAM
The Henske laboratory is focused on the cell biology and biochemistry of Tuberous Sclerosis Complex (TSC), Lymphangioleiomyomatosis (LAM) and Birt-Hogg-Dube Syndrome (BHD).Tuberous Sclerosis Complex (TSC) is a tumor suppressor gene syndrome with a wide spectrum of devastating clinical manifestations, many of which are age-related. TSC is often diagnosed in childhood when patients present with infantile seizures, mental retardation, or autism. Cardiac rhabdomyomas, often observed in infancy, spontaneously regress. In the kidney, benign angiomyolipomas and cysts occur frequently, and malignant angiomyolipomas and renal cell carcinomas are less common. A particularly striking manifestation of TSC is pulmonary lymphangioleiomyomatosis (LAM), which is observed almost exclusively in women. LAM can also occur in women who do not have TSC (sporadic LAM). LAM is characterized by benign smooth muscle cell proliferation in the lungs, which thicken the alveolar wall and reduce gas exchange, and by cystic degeneration of the lungs, resulting in lung collapse. LAM patients often become oxygen-dependent.The TSC Signaling Pathway. TSC2 encodes tuberin, TSC1 encodes hamartin. Rheb (Ras homology enriched in brain) is the target of TSC2's highly conserved GTPase-activating domain. By inhibiting Rheb, the TSC1/TSC2 complex also inhibits the mammalian target of rapamycin (mTOR). mTOR is a kinase that regulates protein synthesis, in part via its regulation of a second kinase, p70S6 kinase (S6K). The phosphorylation of p70S6K by mTOR stimulates translational initiation and contributes to cell growth.Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant tumor suppressor gene syndrome characterized by hamartomas of skin follicles (fibrofolliculomas), spontaneous pneumothorax (lung collapse), and renal cell carcinoma (RCC). Unlike most other genetic disorders associated with renal tumors, BHD patients develop multiple histologic tumor types, including oncocytomas (which are considered benign) and chromophobe, clear cell and papillary carcinomas. The BHD gene was cloned in 2002. Nearly all reported human germline BHD mutations are predicted to result in premature protein truncation.