Editors' ChoiceTranscriptional Regulation

TGF-beta and Myc Control p15Ink4b Expression

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Science's STKE  27 Mar 2001:
Vol. 2001, Issue 75, pp. tw1
DOI: 10.1126/stke.2001.75.tw1

Although originally characterized as a protein involved in promoting tumor cell growth, transforming growth factor-β (TGF-β) also has cytostatic activities that lead to cell growth arrest in G2. Amounts of p15Ink4b, a cyclin-dependent kinase (CDK) inhibitor, increase in response to TGF-β, and concomitantly, amounts of Myc decrease, but the mechanism behind the control of p15Ink4b expression has remained a mystery. Staller et al. found that Miz-1, a transcription factor that can associate with Myc, binds to an initiator element in the p15Ink4b promoter, and induces the expression of p15Ink4b. However, when bound to Myc, Miz-1 could not associate with the histone N-acetyltransferase transcriptional coactivator p300, which resulted in greatly decreased p15Ink4b expression. Expression of Myc mutants that do not bind Miz-1 failed to repress p15Ink4b expression. Seoane et al. demonstrated that TGF-β treatment removed Myc-dependent repression of Miz-1-directed p15Ink4b expression. Additionally Seoane et al. found that Smad proteins, transcription factors in the TGF-β signaling pathway, bound to Miz-1, suggesting that Smads and Miz-1 may cooperate in promoting p15Ink4b expression. The data also suggest that the interaction of Myc and Miz-1 could become a clinically relevant target for cancer drug design.

P. Staller, K. Peukert, A. Kiermaier, J. Seoane, J. Lukas, H. Karsunky, T. Möröy, J. Bartek, J. Massagué, F. Hänel, M. Eilers, Repression of p15INK4b expression by Myc through association with Miz-1. Nature Cell Biol. 3, 392-399 (2001). [Online Journal]

J. Seoane, C. Pouponnot, P. Staller, M. Schader, M. Eilers, J. Massagué, TGF-β influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nature Cell Biol. 3, 400-408 (2001). [Online Journal]