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.