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, and tumor suppression. 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.
Birchenall-Roberts
Maria C
MC
Basic Research Program, SAIC-Frederick, NCI-Frederick, Frederick, Maryland 21702, USA. birchena@mail.ncifcrf.gov
Fu
Tao
T
Bang
Ok-Sun
OS
Dambach
Michael
M
Resau
James H
JH
Sadowski
Cari L
CL
Bertolette
Daniel C
DC
Lee
Ho-Jae
HJ
Kim
Seong-Jin
SJ
Ruscetti
Francis W
FW
D001665:Binding Sites; D002453:Cell Cycle; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002762:Cholecalciferol / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D006801:Humans; D012097:Repressor Proteins / Q000737:chemistry / Q000502:physiology*; D015398:Signal Transduction; D051899:Smad2 Protein; D051900:Smad3 Protein; D015534:Trans-Activators / Q000737:chemistry / Q000502:physiology*; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins
D004268:DNA-Binding Proteins; D012097:Repressor Proteins; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; C508960:TGFB1 protein, human; C000624653:TSC2 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D002762:Cholecalciferol