Tumor necrosis factor- (TNF-) is a proinflammatory cytokine that is linked to inhibition of erythroid differentiation and may contribute to the pathogenesis of anemia of chronic inflammation, cancer and hematopoietic diseases. However, the mechanism of TNF--inhibited erythroid differentiation has not been elucidated. The induction of erythroid differentiation in CD34+ hematopoietic stem cells (HSC) by human recombinant erythropoietin (hrEPO) was used in the treatment of anemia in these pathologies. Based on clinical trials, the serious side effects and resistance of hrEPO have emerged as a major concern. In addition, the hrEPO therapy in the treatment of cancer-associated anemia increases tumor progression resulting in decreased survival. For these reasons, it is important to identify potential target molecules of TNF-inhibited erythroid differentiation for inflammation, cancer, and hematopoietic disease related anemia. Our previous data suggested that TNF-inhibited activin A- or EPO-mediated erythorid differentiation in primary CD34+ HSC cells and hematopoietic progenitor cell line K562. Activin A (or erythroid differentiation factor) is a member of the transforming growth factor- superfamily that induces the erythroid differentiation of hematopoietic stem/progenitor cells. The markers of erythroid differentiation are globin and glycophorin A. Our previous results also showed that TNF- induced CD24 expression at the RNA and protein level in K562 cells. A luciferase reporter assay showed that overexpression of CD24 decreased activin A-induced -globin promoter activity in K562 cells. These results imply that CD24 may involve in TNF--inhibited erythroid differentiation. CD24 is a glycoprotein, which is glycosyl-phosphatidylinositol-anchored on cell membrane. CD24 is thought to have a role in immune system and tumorigenesis. Our 103 Research Project of Ministry of Science and Technology focused on “to delineate how TNF- regulates CD24 gene expression”. We will further continue this work. Our preliminary results revealed that overexpression of CD24 enhanced TNF- inhibition of activin A-induced promoter activity and expression of -globin in K562 cells. Knockdown of CD24 eliminated TNF- inhibition of activin A-induced expression of glycophorin A in K562 cells. Similarly, knockdown of CD24 eliminated TNF- inhibition of activin A- or EPO-induced -globin expression in primary CD34+ HSC cells. Overexpression of CD24 increased phosphorylation of FAK and ERK proteins. ERK inhibitor PD98059 can abolish TNF- inhibition of activin A-induced -globin promoter activity in CD24 overexpressing K562 cells. Taken together, these data imply that CD24 may be played a novel role in TNF--inhibited erythroid differentiation. In this proposal, we will study the role of CD24 in TNF--inhibited erythroid differentiation and its signaling pathway. The objectives of this program project are (1) to identify the role of CD24 in TNF--inhibited erythroid differentiation. (2) to study mechanism of the CD24 signaling pathway in TNF--inhibited erythroid differentiation.
|Effective start/end date||8/1/15 → 7/31/16|
- Activin A
- Erythroid differentiation
- K562 cells
- CD34+ HSC cells
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