TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b.

TY - JOUR

T1 - TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b.

AU - Seoane, J

AU - Pouponnot, C

AU - Staller, P

AU - Schader, M

AU - Eilers, M

AU - Massagué, J

N1 - Keywords: Animals; Base Sequence; COS Cells; Carrier Proteins; Cell Cycle Proteins; Cercopithecus aethiops; Cyclin-Dependent Kinase Inhibitor p15; Cyclin-Dependent Kinase Inhibitor p16; Cyclin-Dependent Kinases; DNA-Binding Proteins; Gene Silencing; Humans; Kruppel-Like Transcription Factors; Mice; Molecular Sequence Data; Promoter Regions (Genetics); Proto-Oncogene Proteins c-myc; Response Elements; Smad2 Protein; Smad3 Protein; Smad4 Protein; Smad7 Protein; Trans-Activation (Genetics); Trans-Activators; Transcription Factors; Transforming Growth Factor beta; Tumor Suppressor Proteins; Zinc Fingers

PY - 2001

Y1 - 2001

N2 - Transforming growth factor-beta (TGFbeta) 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 TGFbeta involve Smad transcription factors that are directly activated by the TGFbeta receptor. Why downregulation of c-myc expression by TGFbeta is required for rapid activation of p15INK4b has remained unknown. Here we provide evidence that TGFbeta 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 TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. Thus, two separate TGFbeta-dependent inputs - Smad-mediated transactivation and relief of repression by Myc - keep tight control over p15INK4b activation.

AB - Transforming growth factor-beta (TGFbeta) 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 TGFbeta involve Smad transcription factors that are directly activated by the TGFbeta receptor. Why downregulation of c-myc expression by TGFbeta is required for rapid activation of p15INK4b has remained unknown. Here we provide evidence that TGFbeta 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 TGFbeta-induced Smad protein complex that recognizes an upstream p15INK4b promoter region and contacts Miz-1. Thus, two separate TGFbeta-dependent inputs - Smad-mediated transactivation and relief of repression by Myc - keep tight control over p15INK4b activation.

U2 - 10.1038/35070086

DO - 10.1038/35070086

M3 - Journal article

C2 - 11283614

SN - 1465-7392

VL - 3

SP - 400

EP - 408

JO - Nature Cell Biology

JF - Nature Cell Biology

IS - 4

ER -