Article abstract
Nature Cell Biology 3, 400 - 408 (2001)
Published online: 13 March 2001 | doi:10.1038/35070086
TGF
influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b
Joan Seoane1, Celio Pouponnot1, Peter Staller2, Manuela Schader2, Martin Eilers2 & Joan Massagué1
Abstract
Transforming growth factor-
(TGF) is a cytokine that arrests epithelial cell division by switching off the proto-oncogene c-myc and rapidly switching on cyclin-dependent kinase (CDK) inhibitors such as p15INK4b. Gene responses to TGF involve Smad transcription factors that are directly activated by the TGF receptor. Why downregulation of c-myc expression by TGF is required for rapid activation of p15INK4b has remained unknown. Here we provide evidence that TGF signalling prevents recruitment of Myc to the p15INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGF-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. Thus, two separate TGF-dependent inputs — Smad-mediated transactivation and relief of repression by Myc — keep tight control over p15INK4b activation.
- Cell Biology Program and Howard Hughes Medical Institute, Memorial Sloan–Kettering Cancer Center, 1275 York Avenue , New York, New York 10021, USA
- Institute of Molecular Biology and Tumour Research , Emil Mankoff Strasse 2, 35033 Marburg , Germany
Correspondence to: Joan Massagué1 e-mail: j-massague@ski.mskcc.org
