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Molecular and Cellular Biology, July 2003, p. 5031-5042, Vol. 23, No. 14
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.14.5031-5042.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

GATA-1-Mediated Proliferation Arrest during Erythroid Maturation

Marcin Rylski,1,2,4 John J. Welch,1 Ying-Yu Chen,1 Danielle L. Letting,1 J. Alan Diehl,3 Lewis A. Chodosh,3 Gerd A. Blobel,1 and Mitchell J. Weiss1*

Division of Hematology, The Children's Hospital of Philadelphia,1 Department of Cancer Biology, Abramson Family Cancer Research Institute,3 University of Pennsylvania, Philadelphia, Pennsylvania 19104,4 Department of Genetics, Faculty of Biology, University of Warmia and Mazury, Olsztyn 10-719, Poland2

Received 6 January 2003/ Returned for modification 7 March 2003/ Accepted 17 April 2003

Transcription factor GATA-1 is essential for erythroid and megakaryocytic maturation. GATA-1 mutations are associated with hematopoietic precursor proliferation and leukemogenesis, suggesting a role in cell cycle control. While numerous GATA-1 target genes specifying mature hematopoietic phenotypes have been identified, how GATA-1 regulates proliferation remains unknown. We used a complementation assay based on synchronous inducible rescue of GATA-1- erythroblasts to show that GATA-1 promotes both erythroid maturation and G1 cell cycle arrest. Molecular studies combined with microarray transcriptome analysis revealed an extensive GATA-1-regulated program of cell cycle control in which numerous growth inhibitors were upregulated and mitogenic genes were repressed. GATA-1 inhibited expression of cyclin-dependent kinase (Cdk) 6 and cyclin D2 and induced the Cdk inhibitors p18INK4C and p27Kip1 with associated inactivation of all G1 Cdks. These effects were dependent on GATA-1-mediated repression of the c-myc (Myc) proto-oncogene. GATA-1 inhibited Myc expression within 3 h, and chromatin immunoprecipitation studies indicated that GATA-1 occupies the Myc promoter in vivo, suggesting a direct mechanism for gene repression. Surprisingly, enforced expression of Myc prevented GATA-1-induced cell cycle arrest but had minimal effects on erythroid maturation. Our results illustrate how GATA-1, a lineage-determining transcription factor, coordinates proliferation arrest with cellular maturation through distinct, interrelated genetic programs.

* Corresponding author. Mailing address: The Children's Hospital of Philadelphia, Division of Hematology, Room 316B ARC, 3615 Civic Center Blvd., Philadelphia, PA 19104. Phone: (215) 590-0565. Fax: (215) 590-4834. E-mail: weissmi{at}email.chop.edu.

Molecular and Cellular Biology, July 2003, p. 5031-5042, Vol. 23, No. 14
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.14.5031-5042.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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