GATA-1-mediated proliferation arrest during erythroid maturation.
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 G(1) 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 p18(INK4C) and p27(Kip1) with associated inactivation of all G(1) 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.
Rylski
Marcin
M
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Welch
John J
JJ
Chen
Ying-Yu
YY
Letting
Danielle L
DL
Diehl
J Alan
JA
Chodosh
Lewis A
LA
Blobel
Gerd A
GA
Weiss
Mitchell J
MJ
D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D002455:Cell Division / Q000502:physiology; D002478:Cells, Cultured; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D004900:Erythroblasts / Q000166:cytology* / Q000502:physiology*; D050981:Erythroid-Specific DNA-Binding Factors; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016259:Genes, myc; D005816:Genetic Complementation Test; D005914:Globins / Q000235:genetics; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D018797:Cell Cycle Proteins; D050763:Cyclin-Dependent Kinase Inhibitor p18; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D050981:Erythroid-Specific DNA-Binding Factors; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D005914:Globins; D018844:Cyclin-Dependent Kinases