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Molecular and Cellular Biology, December 2008, p. 7286-7295, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00752-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Myc Inhibits p27-Induced Erythroid Differentiation of Leukemia Cells by Repressing Erythroid Master Genes without Reversing p27-Mediated Cell Cycle Arrest{triangledown} ,{ddagger}

Juan C. Acosta,1,{dagger},§ Nuria Ferrándiz,1,{dagger} Gabriel Bretones,1 Verónica Torrano,1 Rosa Blanco,1 Carlos Richard,2 Brenda O'Connell,3 John Sedivy,3 M. Dolores Delgado,1 and Javier León1*

Cancer Molecular Biology Group, Department of Molecular Biology, Instituto de Biomedicina y Biotecnología de Cantabria, Universidad de Cantabria-CSIC-IDICAN, Santander, Spain,1 Department of Hematology, Hospital Universitario Marqués de Valdecilla-IFIMAV, Santander, Spain,2 Department of Molecular Biology, Cell Biology, and Biochemistry and Center for Genomics and Proteomics, Brown University, Providence, Rhode Island3

Received 9 May 2008/ Returned for modification 13 June 2008/ Accepted 28 September 2008

Inhibition of differentiation has been proposed as an important mechanism for Myc-induced tumorigenesis, but the mechanisms involved are unclear. We have established a genetically defined differentiation model in human leukemia K562 cells by conditional expression of the cyclin-dependent kinase (Cdk) inhibitor p27 (inducible by Zn2+) and Myc (activatable by 4-hydroxy-tamoxifen). Induction of p27 resulted in erythroid differentiation, accompanied by Cdk inhibition and G1 arrest. Interestingly, activation of Myc inhibited p27-mediated erythroid differentiation without affecting p27-mediated proliferation arrest. Microarray-based gene expression indicated that, in the presence of p27, Myc blocked the upregulation of several erythroid-cell-specific genes, including NFE2, JUNB, and GATA1 (transcription factors with a pivotal role in erythropoiesis). Moreover, Myc also blocked the upregulation of Mad1, a transcriptional antagonist of Myc that is able to induce erythroid differentiation. Cotransfection experiments demonstrated that Myc-mediated inhibition of differentiation is partly dependent on the repression of Mad1 and GATA1. In conclusion, this model demonstrates that Myc-mediated inhibition of differentiation depends on the regulation of a specific gene program, whereas it is independent of p27-mediated cell cycle arrest. Our results support the hypothesis that differentiation inhibition is an important Myc tumorigenic mechanism that is independent of cell proliferation.

* Corresponding author. Mailing address: Dpto. de Biología Molecular, Facultad de Medicina, Avda. Cardenal Herrera Oria s/n, 39011 Santander, Spain. Phone: 34-942-201952. Fax: 34-942-201945. E-mail: leonj{at}unican.es

{triangledown} Published ahead of print on 6 October 2008.

{ddagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{dagger} J.C.A. and N.F. contributed equally to this study.

§ Present address: MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College, Hammersmith Campus, London, United Kingdom.

Molecular and Cellular Biology, December 2008, p. 7286-7295, Vol. 28, No. 24
0270-7306/08/$08.00+0     doi:10.1128/MCB.00752-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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