Repression of c-Kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation

Veerendra Munugalavadla, Louis C. Dore, Bai Lin Tan, Li Hong, Melanie Vishnu, Mitchell J. Weiss, Reuben Kapur

Research output: Contribution to journalArticle

85 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)6747-6759
Number of pages13
JournalMolecular and Cellular Biology
Volume25
Issue number15
DOIs
StatePublished - Aug 2005

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Stem Cell Factor
Cell Proliferation
Erythropoietin
Activator Appliances
G1 Phase Cell Cycle Checkpoints
Erythroblasts
Chromatin Immunoprecipitation
Regulator Genes
Cell Cycle Checkpoints
Genes
Cell Cycle
Cytokines
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cell Biology

Cite this

Repression of c-Kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation. / Munugalavadla, Veerendra; Dore, Louis C.; Tan, Bai Lin; Hong, Li; Vishnu, Melanie; Weiss, Mitchell J.; Kapur, Reuben.

In: Molecular and Cellular Biology, Vol. 25, No. 15, 08.2005, p. 6747-6759.

Research output: Contribution to journalArticle

Munugalavadla, Veerendra ; Dore, Louis C. ; Tan, Bai Lin ; Hong, Li ; Vishnu, Melanie ; Weiss, Mitchell J. ; Kapur, Reuben. / Repression of c-Kit and its downstream substrates by GATA-1 inhibits cell proliferation during erythroid maturation. In: Molecular and Cellular Biology. 2005 ; Vol. 25, No. 15. pp. 6747-6759.
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