TGF beta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15(INK4b)

Transforming growth factor-beta (TGF beta) is a cytokine that arrests epith elial cell division by switching off the proto-oncogene c-myc and rapidly s witching on cyclin-dependent kinase (CDK) inhibitors such as p15(INK4b). Ge ne responses to TGF beta involve Smad transcription factors that are direct ly activated by the TGF beta receptor. Why downregulation of c-myc expressi on by TGF beta is required for rapid activation of p15(INK4b) has remained unknown. Here we provide evidence that TGF beta signalling prevents recruit ment of Myc to the p15(INK4b) transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcr iptional activation by a TGF beta -induced Smad protein complex that recogn izes an upstream p15(INK4b) promoter region and contacts Miz-1. Thus, two s eparate TGF beta -dependent inputs - Smad-mediated transactivation and reli ef of repression by Myc - keep tight control over p15(INK4b) activation.