MAPK-mediated phosphorylation of GATA-1 promotes Bcl-XL expression and cell survival.
In the interleukin 3-dependent hematopoietic cell line Ba/F3, inhibition of mitogen-activated protein kinase, a member of the MAPK/c-Jun N-terminal kinase/stress-activated protein kinase kinase family that plays an important role in cell growth and death control, rapidly leads to severe apoptosis. However, most of the antiapoptotic substrates of MAPK remain to be identified. Here we report that, upon interleukin-3 stimulation of Ba/F3 cells, the transcription factor GATA-1 is strongly phosphorylated at residue serine 26 by a MAPK-dependent pathway. Phosphorylation of GATA-1 increases GATA-1-mediated transcription of the E4bp4 survival gene without significantly changing the DNA-binding affinity of GATA-1. Further characterization of GATA-1 phosphorylation site mutants revealed that the antiapoptotic function of GATA-1 is strongly dependent upon its phosphorylation at the Ser-26 position and is probably mediated through its up-regulation of Bcl-X(L) expression. Taken together, our data demonstrate that MAPK-dependent GATA-1 phosphorylation is important for its transactivation of the E4bp4 gene, Bcl-X(L) expression and cell survival. Therefore, GATA-1 may represent a novel MAPK substrate that plays an essential role in a cytokine-mediated antiapoptotic response.
Yu
Yung-Luen
YL
Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
Chiang
Yun-Jung
YJ
Chen
Yu-Chun
YC
Papetti
Michael
M
Juo
Chiun-Gung
CG
Skoultchi
Arthur I
AI
Yen
Jeffrey J Y
JJ
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D050981:Erythroid-Specific DNA-Binding Factors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D051790:G-Box Binding Factors; D050982:GATA1 Transcription Factor; D005786:Gene Expression Regulation; D007377:Interleukin-3 / Q000494:pharmacology; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D010766:Phosphorylation; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051020:bcl-X Protein
D050976:Basic-Leucine Zipper Transcription Factors; C494812:Bcl2l1 protein, mouse; D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D051790:G-Box Binding Factors; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D007377:Interleukin-3; C497441:Nfil3 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051020:bcl-X Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases