Tuberous sclerosis complex 2 gene product interacts with human SMAD proteins - A molecular link of two tumor suppressor pathways

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)-beta1 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-beta1-responsive genes such as p21(CIP). Inhibition of tuberin expression by Tsc2 antisense greatly reduces the ability of TGF-beta to transcriptionally regulate p21(CIP), p27(KIP), and cyclin A leading to an abrogation of the antiproliferative effects of TGF-beta1. Also, inhibition of tuberin expression during stimulation of monocytic differentiation with vitamin D-3 and TGF-beta1 significantly impaired myeloid cell growth inhibition and differentiation. Together, the data demonstrate the presence of a novel activation process following TGF-beta1 stimulation that requires tuberin-dependent activity.