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Molecular and Cellular Biology, August 2005, p. 6747-6759, Vol. 25, No. 15
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.15.6747-6759.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Repression of c-Kit and Its Downstream Substrates by GATA-1 Inhibits Cell Proliferation during Erythroid Maturation

Veerendra Munugalavadla,1,3* Louis C. Dore,4 Bai Lin Tan,1,3,{dagger} Li Hong,1,3,{dagger} Melanie Vishnu,5 Mitchell J. Weiss,4,5 and Reuben Kapur1,2,3*

Department of Pediatrics, Herman B Wells Center for Pediatric Research,1 Department of Molecular Biology and Biochemistry,2 Indiana University School of Medicine, Indianapolis, Indiana,3 Children's Hospital of Philadelphia, Division of Hematology,4 University of Pennsylvania, Philadelphia, Pennsylvania5

Received 17 November 2004/ Accepted 6 May 2005

Stem cell factor (SCF), erythropoietin (Epo), and GATA-1 play an essential role(s) in erythroid development. We examined how these proteins interact functionally in G1E cells, a GATA-1– erythroblast line that proliferates in an SCF-dependent fashion and, upon restoration of GATA-1 function, undergoes GATA-1 proliferation arrest and Epo-dependent terminal maturation. We show that SCF-induced cell cycle progression is mediated via activation of the Src kinase/c-Myc pathway. Restoration of GATA-1 activity induced G1 cell cycle arrest coincident with repression of c-Kit and its downstream effectors Vav1, Rac1, and Akt. Sustained expression of each of these individual signaling components inhibited GATA-1-induced cell cycle arrest to various degrees but had no effects on the expression of GATA-1-regulated erythroid maturation markers. Chromatin immunoprecipitation analysis revealed that GATA-1 occupies a defined Kit gene regulatory element in vivo, suggesting a direct mechanism for gene repression. Hence, in addition to its well-established function as an activator of erythroid genes, GATA-1 also participates in a distinct genetic program that inhibits cell proliferation by repressing the expression of multiple components of the c-Kit signaling axis. Our findings reveal a novel aspect of molecular cross talk between essential transcriptional and cytokine signaling components of hematopoietic development.

* Corresponding author. Mailing address: Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Cancer Research Institute, 1044 W. Walnut Street, Room 425, Indianapolis, IN 46202. Phone: (317) 274-4658. Fax: (317) 274-8679. E-mail for Reuben Kapur: rkapur{at}iupui.edu. E-mail for Veerendra Munugalavadla: vmunugal{at}iupui.edu.

{dagger} B.L.T. and L.H. contributed equally to this work and should be considered co-third authors.

Molecular and Cellular Biology, August 2005, p. 6747-6759, Vol. 25, No. 15
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.15.6747-6759.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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