Hypoxia induces erythroid‐specific 5‐aminolevulinate synthase expression in human erythroid cells through transforming growth factor‐β signaling

Hypoxia induces expansion of erythroid precursor cells through erythropoietin production. However, it has also been suggested that hypoxia could enhance hemoglobin production in erythroid cells directly. To identify the molecules that are involved in hemoglobin production under hypoxia, we examined the expression profile of mRNAs in YN‐1 human erythroleukemia cells under hypoxia. DNA array analysis revealed that the expression of transforming growth factor (TGF)‐β1 and mitoferrin, which is a mitochondrial iron transporter, was induced after 6 h under hypoxia in YN‐1 cells, whereas the increased expression of erythroid‐specific 5‐aminolevulinate synthase (ALAS2) and γ‐globin mRNAs was observed after 48 h. Further analysis revealed that hypoxia enhanced the accumulation of TGF‐β1 in the culture medium of cells of the YN‐1‐0‐A line, which was a clonal variant of YN‐1 and could be maintained in serum‐free medium. Moreover, exogenous TGF‐β1 induced hemoglobinization and the expression of ALAS2 mRNA in YN‐1‐0‐A cells, but not of γ‐globin and mitoferrin mRNAs. Importantly, a specific inhibitor of intracellular TGF‐β signaling markedly reduced the degree of the hypoxia‐mediated increase in the expression of ALAS2 mRNA in YN‐1‐0‐A cells. On the other hand, nonhypoxic inducer of hypoxia‐inducible factor 1 increased the expression of mitoferrin mRNA but not of TGF‐β1 mRNA in YN‐1 cells under normoxia, suggesting that mitoferrin mRNA expression may be regulated by hypoxia‐inducible factor 1. Thus, our data suggest that hypoxia induces the expression of TGF‐β1 and mitoferrin mRNAs through separate mechanisms in erythroid cells. TGF‐β1 subsequently induces ALAS2 expression, which may contribute to terminal differentiation of erythroid cells.