MAPK-mediated Phosphorylation of GATA-1 Promotes Bcl-X Expression and Cell Survival

Abstract

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/stressactivated 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.

The transcription factor GATA-1 is overexpressed in breast carcinomas and contributes to survivin upregulation via a promoter polymorphism

“…Interestingly, the anti-apoptotic function of GATA-1 has been found to be strongly dependent upon its phosphorylation at the serine 26 position (Yu et al, 2005). Here, we show that GATA-1 stimulates survivin gene transcription when phosphorylated on serine 26, indicating an upstream role for MAPK pathway in survivin overexpression in breast cancer cells.…”

“…In erythroid cells exposed to erythropoietin, GATA-1 is the final effector of signalling pathways involving phosphatidylinositol-3-phosphate/protein kinase, B-Akt (Zhao et al, 2006), which phosphorylates the transcription factor on serine 310 (Kadri et al, 2005), and mitogen-activated protein kinase (MAPK) cascade, which phosphorylates GATA-1 on serine 26 and 178 (Towatari et al, 2004;Yu et al, 2005). Interestingly, the anti-apoptotic function of GATA-1 has been found to be strongly dependent upon its phosphorylation at the serine 26 position (Yu et al, 2005).…”

“…GATA-1 was shown to be activated by phosphorylation on various serine residues (Crossley and Orkin, 1994;Towatari et al, 2004;Kadri et al, 2005). GATA-1 has a role in cell survival by regulating promoters of several anti-apoptotic genes such as nitric-oxide synthase, antioxidant enzymes and anti-apoptotic proteins such as Bcl-X L (Yu et al, 2005). We generated the three principal constitutively active forms of GATA-1 by replacement of Ser26, 178 and 310 with glutamate residues.…”

Repeated Unpredictable Stress and Antidepressants Differentially Regulate Expression of the Bcl-2 Family of Apoptotic Genes in Rat Cortical, Hippocampal, and Limbic Brain Structures

“…In vitro studies have shown that the Bcl-xl gene promoter is regulated by NF-kB and its expression is regulated by the MAPK signaling pathway (Marinari et al, 2004;Yu et al, 2005) The Bcl-2 promoter contains a CRE that mediates its responsivity to the transcription factor (CREB) (Bonni et al, 1999;Riccio et al, 1999). Withdrawal of trophic support as well as an inhibition of CREB transcription triggers apoptosis in neurons.…”

Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6

“…These results indicate that GATA-6 is a component of protein complexes bound to the GATA sites of the Nox1 promoter. Phosphorylation of GATA-1, -2, -3 and -4 is known to modulate their DNA-binding and protein-protein interactions resulting in cell-and gene-specific transcriptions (Morimoto et al, 2000;Patient and McGhee, 2002;Yu et al, 2005). Likewise, GATA-6 contains consensus ERK phosphorylation sites (PXS/TP: PYS 120 P, PYS 192 P and PMT 369 P) (Suzuki et al, 1996).…”