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

Abstract

Transforming growth factor-β (TGFβ) 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 p15^INK4b. Gene responses to TGFβ involve Smad transcription factors that are directly activated by the TGFβ receptor. Why downregulation of c-myc expression by TGFβ is required for rapid activation of p15^INK4b has remained unknown. Here we provide evidence that TGFβ signalling prevents recruitment of Myc to the p15^INK4b transcriptional initiator by Myc-interacting zinc-finger protein 1 (Miz-1). This relieves repression and enables transcriptional activation by a TGFβ-induced Smad protein complex that recognizes an upstream p15^INK4b promoter region and contacts Miz-1. Thus, two separate TGFβ-dependent inputs — Smad-mediated transactivation and relief of repression by Myc — keep tight control over p15^INK4b activation.