Tuberous Sclerosis Complex 2 Gene Product Interacts with Human SMAD Proteins

Abstract

Tuberin ( TSC2) is a tumor suppressor gene. At the cellular level, tuberin is required as a critical regulator of cell growth, neuronal differentiation (Soucek, T., Holzl, G., Bernaschek, G., and Hengstschlager, M. (1998) Oncogene 16, 2197–2204), and tumor suppression (Crino, P. B., and Henske, E. P. (1999) Neurology 53, 1384–1390). Here we report a critical role for tuberin in late stage myeloid cell differentiation. Tuberin strongly augments transforming growth factor (TGF)-β1 signal transduction pathways, including SMAD activation. We also demonstrate that the amino-terminal region of tuberin interacts specifically with the MH2 domain of SMAD2 and SMAD3 proteins to regulate TGF-β1-responsive genes such as p21 CIP . Inhibition of tuberin expression by Tsc2 antisense greatly reduces the ability of TGF-β to transcriptionally regulate p21 CIP , p27 KIP , and cyclin A leading to an abrogation of the antiproliferative effects of TGF-β1. Also, inhibition of tuberin expression during stimulation of monocytic differentiation with vitamin D 3 and TGF-β1 significantly impaired myeloid cell growth inhibition and differentiation. Together, the data demonstrate the presence of a novel activation process following TGF-β1 stimulation that requires tuberin-dependent activity.