The proinflammatory cytokine tumor necrosis factor-alpha (TNF-α) plays a physiological role in cell proliferation, apoptosis, inflammation and tumorigenesis. Anemia is considered as a common symptom induced by inflammation, cancer and hematopoietic diseases. Inflammation, cancer and hematopoietic disease related anemia were shown to be induced by TNF-α. However, the molecular mechanism of TNF-α-inhibited erythroid differentiation in hematopoietic stem/progenitor cells has not been elucidated. The erythroid differentiation of hematopoietic stem/progenitor cells is induced by erythropoietin (EPO). EPO was used in the treatment of inflammation, cancer and hematopoietic disease related anemia. However, the serious side effects and resistance of EPO were recently described in distinct studies. Indeed, several studies showed the increased mortality came from accelerated progression of cancer. Unexpectedly, the use of EPO in patients might increase the risk of cancer-associated death. Thus, the molecular mechanisms of TNFα-inhibited erythroid differentiation need to be further elucidated in order to identify potential target molecules for inflammation and cancer as well as hematopoietic disease related anemia. Our preliminary results revealed that TNF-α suppressed erythorid differentiation in hematopoietic stem cells (HSC CD34+ cells) and hematopoietic progenitor cell line K562. CD24 is a glycosyl-phosphatidylinositol-anchored cell membrane glycoprotein, and is regarded as a lymphoid differentiation marker. CD24 has also been implicated in tumorigenesis, progression, invasion and metastasis. Our reporter assay showed that TNF-α induced promoter activity of the CD24 gene in K562 cells. TNF-α induced CD24 expression, both at the RNA and protein level. The binding of NF-κBp65 to the CD24 promoter induced by TNF-α in K562 cells was demonstrated by the chromatin immunoprecipitation assay. Furthermore, CD24 overexpression inhibited ζ-globin promoter activity as well as increased tyrosine phosphorylated signals and GATA-2 RNA level. GATA-2 is a transcription factor required for the survival and proliferation of hematopoietic stem/progenitor cells. Taken together, these results imply that CD24 may be played a novel role in TNF-α-inhibited erythroid differentiation. In this proposal, we will study the role of CD24 in TNFα-inhibited erythroid differentiation. The objectives of this program project are: (1) to delineate how TNF-α regulates CD24 gene expression (2) to identify the role of CD24 in TNF-α-inhibited erythroid differentiation (3) to study the molecular mechanism of CD24-inhibited erythroid differentiation
|Effective start/end date||8/1/14 → 7/31/15|
- Tumor necrosis factor-alpha
- Erythroid differentiation
- Hematopoietic progenitor cell line K562
- Hematopoietic stem cells
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