Direct interaction of c-Myc with Smad2 and Smad3 to inhibit TGF-beta-mediated induction of the CDK inhibitor p15(Ink4B)

The c-Myc oncogene has been implicated in the genesis of diverse human tumors. Ectopic expression of the c-Myc gene in cultured epithelial cells causes resistance to the antiproliferative effects of TGF-beta. However, little is known about the precise mechanisms of c-Myc-mediated TGF-beta resistance...

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Bibliographic Details
Published in:Molecular cell 2002-01, Vol.9 (1), p.133-143
Main Authors: Feng, Xin-Hua, Liang, Yao-Yun, Liang, Min, Zhai, Weiguo, Lin, Xia
Format: Article
Language:English
Subjects:
Cell Cycle Proteins - genetics
Cell Cycle Proteins - metabolism
Cell Line
Cyclin-Dependent Kinase Inhibitor p15
Cyclin-Dependent Kinase Inhibitor p16 - genetics
Cyclin-Dependent Kinase Inhibitor p16 - metabolism
Cyclin-Dependent Kinases - antagonists & inhibitors
DNA-Binding Proteins - genetics
DNA-Binding Proteins - metabolism
Humans
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins c-myc - genetics
Proto-Oncogene Proteins c-myc - metabolism
Receptors, Transforming Growth Factor beta - genetics
Receptors, Transforming Growth Factor beta - metabolism
Signal Transduction
Smad2 Protein
Smad3 Protein
Sp1 Transcription Factor - genetics
Sp1 Transcription Factor - metabolism
Trans-Activators - genetics
Trans-Activators - metabolism
Transforming Growth Factor beta - genetics
Transforming Growth Factor beta - metabolism
Tumor Suppressor Proteins
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Summary:The c-Myc oncogene has been implicated in the genesis of diverse human tumors. Ectopic expression of the c-Myc gene in cultured epithelial cells causes resistance to the antiproliferative effects of TGF-beta. However, little is known about the precise mechanisms of c-Myc-mediated TGF-beta resistance. In this study, we reveal that c-Myc physically interacts with Smad2 and Smad3, two specific signal transducers involved in TGF-beta signaling. Through its direct interaction with Smads, c-Myc binds to the Sp1-Smad complex on the promoter of the p15(Ink4B) gene, thereby inhibiting the TGF-beta-induced transcriptional activity of Sp1 and Smad/Sp1-dependent transcription of the p15(Ink4B) gene. These results suggest that oncogenic c-Myc promotes cell growth and cancer development partly by inhibiting the growth inhibitory functions of Smads.
ISSN:1097-2765
DOI:10.1016/S1097-2765(01)00430-0