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

@article{citeulike:454001, 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.}, author = {Munugalavadla, Veerendra and Dore, Louis C. and Tan, Bai L. and Hong, Li and Vishnu, Melanie and Weiss, Mitchell J. and Kapur, Reuben}, citeulike-article-id = {454001}, citeulike-linkout-0 = {http://dx.doi.org/10.1128/MCB.25.15.6747}, citeulike-linkout-1 = {http://mcb.asm.org/cgi/content/abstract/25/15/6747}, citeulike-linkout-2 = {http://view.ncbi.nlm.nih.gov/pubmed/16024808}, citeulike-linkout-3 = {http://www.hubmed.org/display.cgi?uids=16024808}, day = {1}, doi = {10.1128/MCB.25.15.6747}, journal = {Mol. Cell. Biol.}, keywords = {c-kit, erythropoiesis, gata1, transcription}, month = {August}, number = {15}, pages = {6747--6759}, posted-at = {2006-01-02 02:03:35}, priority = {2}, title = {Repression of c-Kit and Its Downstream Substrates by GATA-1 Inhibits Cell Proliferation during Erythroid Maturation}, url = {http://dx.doi.org/10.1128/MCB.25.15.6747}, volume = {25}, year = {2005} }

TY - JOUR ID - citeulike:454001 L3 - citeulike-article-id:454001 N2 - 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. IS - 15 JF - Mol. Cell. Biol. EP - 6759 TI - Repression of c-Kit and Its Downstream Substrates by GATA-1 Inhibits Cell Proliferation during Erythroid Maturation VL - 25 SP - 6747 KW - c-kit KW - erythropoiesis KW - gata1 KW - transcription AU - Munugalavadla, Veerendra AU - Dore, Louis AU - Tan, Bai AU - Hong, Li AU - Vishnu, Melanie AU - Weiss, Mitchell AU - Kapur, Reuben PY - 2005/08/01/ UR - http://dx.doi.org/10.1128/MCB.25.15.6747 ER -