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Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter

Oncogene volume 22, pages 351–360 (2003)Cite this article

Abstract

Inhibition of cellular differentiation is one of the well-known biological activities of c-Myc-family proteins. We show here that Myc represses differentiation-induced expression of the cyclin-dependent kinase (CDK) inhibitor p21CIP1 (CDKN1A, p21), known to play an important role in cell fate decisions during growth and differentiation, in hematopoietic cells. Our results demonstrate that the c-Myc-responsive region is situated in the p21 core promoter. c-Myc binds to this region in vitro and in vivo through interaction with the initiator-binding Zn-finger transcription factor Miz-1, which associates directly with the promoter. Association of Myc with the promoter in vivo correlates inversely with p21 expression. Using mutants of c-Myc with impaired binding to Miz-1, our results further show that repression of p21 promoter/reporters as well as the endogenous p21 gene by Myc depends on interaction with Miz-1. Expression of Miz-1 increases during hematopoietic differentiation and Miz-1 activates the p21 promoter under conditions of low Myc levels, indicating a positive role for free Miz-1 in this process. In conclusion, repression of differentia-tion-induced p21 expression through Miz-1 may be an important mechanism by which Myc blocks diffe-rentiation.

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Acknowledgements

We thank Drs WS El-Deiry, B Lüscher, P Staller, X-F Wang, G Westin, B Westermark and J Ziegelbauer for reagents. We also thank Dr J Botling, Åsa Böker and A Castell for experimental support, and Drs D Balciunas, D Grander, B Lüscher, A Moustakas, F Öberg, H Ronne, C Svensson and G Westin for valuable discussions. This work was supported by grants from the Swedish Cancer Society, Deutsche Forschungsmeinschaft, and Grants PM98-109 and FD97-1987 from the Spanish Government.

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Authors and Affiliations

  1. Department of Plant Biology, Swedish University of Agricultural Sciences, Uppsala, Sweden

    Siqin Wu, Cihan Cetinkaya, Natalie von der Lehr, Fuad Bahram & Lars-Gunnar Larsson

  2. Departamento de Biologia Molecular and Unidad Asociada-CSIC, Universidad de Cantabria, Santander, Spain

    Maria J Munoz-Alonso & Javier Leon

  3. Institute for Molecular Biology and Tumour Research, Marburg, Germany

    Vincent Beuger & Martin Eilers

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  1. Siqin Wu
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  2. Cihan Cetinkaya
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  3. Maria J Munoz-Alonso
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Correspondence to Lars-Gunnar Larsson.

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Wu, S., Cetinkaya, C., Munoz-Alonso, M. et al. Myc represses differentiation-induced p21CIP1 expression via Miz-1-dependent interaction with the p21 core promoter. Oncogene 22, 351–360 (2003). https://doi.org/10.1038/sj.onc.1206145

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