Novel Transcriptional Regulatory Pathways of IL-3-Dependent Survival Responses
In the past several years, we devoted in the identification of cellular transcriptional factors that could recognize the CES2/E2A-HLF binding element (CBE) and were involved in apoptotic regulation. We firstly demonstrated the existence of multiple binding complexes of CBE in various cell types and tissues, and identified cAMP-responsive element binding protein (CREB) as a component in one major CBE-complex of hematopoietic cell lines. Stimulation of hematopoietic cells with IL-3 promptly induced phosphorylation of CREB at serine 133 partially via a PKA-dependent pathway. Alteration of function of PKA or CREB strongly correlated with the survival capacity of hematopoietic cells. Secondly, we explored the IL-3-dependent transactivation mechanism of another CBE-binding protein, E4BP4. We demonstrated that E4bp4 was regulated by IL-3 mainly at the transcriptional level. Promoter mapping and binding analyses revealed that GATA-1 and GATA-2 proteins were responsible for E4bp4 transcription via a conserved GATA site. Functional assays also suggested that GATA-1 not only modulated the expression of the E4bp4 gene but also controlled apoptosis. The discovery of involvement of CREB and GATA transcriptional factors in IL-3’s survival responses extends our knowledge on the anti-apoptotic pathways in hematopoietic cells and may contribute to our further understanding of the process of hematopoiesis and leukemogenesis.
KeywordsHematopoietic Cell Electrophoretic Mobility Shift Assay Survival Response Antiapoptotic Activity BalF3 Cell
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