EXPRESSION OF THE TSC2 PRODUCT TUBERIN AND ITS TARGET RAP1 IN NORMAL HUMAN TISSUES

The tuberous sclerosis-2 (TSC2) gene is linked to tuberous sclerosis ( TSC), dominantly inherited genetic syndrome in which inactivation of t he normal TSC2 allele is associated with the development of mostly ben ign tumors and focal dysplasias. TSC2 encodes the protein tuberin, whi ch is a widely expressed 180-kd polypeptide that exhibits specific GTP ase activating activity toward Rap1 in vitro and co-localizes with Rap 1 in cultured cells. In this study, we have performed immunohistochemi cal analyses, using affinity-purified anti-tuberin antibodies, to stud y the distribution of tuberin in a panel of normal human organs that a re commonly affected by TSC. Cryosections indicated that tuberin is wi dely expressed at low levels. More intense staining of tuberin, in the cryosections and in paraffin sections, was observed in the small bloo d vessels of many organs, including the kidney, skin, and adrenal glan d. High levels of tuberin were also detected in cortical neurons and c erebellar Purkinje cells. These findings imply that loss-of-function m utations in TSC2 might lead to the development of highly vascularized tumors, subcortical tubers, and focal atrophy of the cerebellar cortex , which are features commonly associated with TSC. Moreover, Rap1 was also found to be highly expressed in many of the same cells that conta ined high levels of tuberin, suggesting a functional interaction betwe en tuberin and Rap1 in these tissues.