Two chronic myelogenous leultaemia cell lines which represent different stages of erythroid differentiation

Endo, Kojin; Harigae, Hideo; Nagai, Tadashi; Fujie, Hiromi; Meguro, Kuniaki; Watanabe, Norimichi; Furuyama, Kazumichi; Kameoka, Junichi; Okuda, Mitsutaka; Hayashi, Norio; Yamamoto, Masayuki; Abe, Keishi

doi:10.1111/j.1365-2141.1993.tb03205.x

Cited by 33 publications

(14 citation statements)

References 27 publications

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“…Recently, we reported that hypoxia increased heme contents in YN‐1 cells after 48 h of incubation [8], which prompted us to examine whether hypoxia induces terminal differentiation of erythroid cells. In this context, it has been reported that YN‐1 cells predominantly produce hemoglobin Bart’s, hemoglobin Portland, and hemoglobin F [7]. Each of these hemoglobins contains γ‐globin chains.…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2009

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A reduction in oxygen supply (hypoxia) is a stress for all mammalian cells, and is associated with vascular disease, pulmonary disease and cancer. To cope with hypoxia, an individual cell changes the expression of the genes involved in glucose metabolism and energy production [1]. On the other hand, hypoxia plays an important role in various biological processes, such as vasculogenesis, iron homeostasis and cell differentiation [1]. In mammals, erythrocytosis is observed when they adapt to hypoxia (e.g. at high altitude), and erythropoietin (EPO) has a pivotal role in the expansion of erythroid precursor cells in bone marrow [2]. 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)-b1 and mitoferrin, which is a mitochondrial iron transporter, was induced after 6 h under hypoxia in YN-1 cells, whereas the increased expression of erythroidspecific 5-aminolevulinate synthase (ALAS2) and c-globin mRNAs was observed after 48 h. Further analysis revealed that hypoxia enhanced the accumulation of TGF-b1 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-b1 induced hemoglobinization and the expression of ALAS2 mRNA in YN-1-0-A cells, but not of c-globin and mitoferrin mRNAs. Importantly, a specific inhibitor of intracellular TGF-b 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-b1 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-b1 and mitoferrin mRNAs through separate mechanisms in erythroid cells. TGF-b1 subsequently induces ALAS2 expression, which may contribute to terminal differentiation of erythroid cells.Abbreviations ALAS2, erythroid-specific 5-aminolevulinate synthase; DMOG, dimethyloxaloylglycine; EPO, erythropoietin; HIF-1, hypoxia-inducible factor 1; HRI, heme regulatory inhibitor; PVDF, poly(vinylidene difluoride); SD, standard deviation; TFR1, transferrin receptor type 1; TGF, transforming growth factor.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2009

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“…1C). Higher heme content may reflect hemoglobin production in YN‐1 and K562 cells [33,34]. In fact, the population of hemoglobin‐positive cells was about 4.4% in YN‐1 cells and 4.9% in K562 cells under basal conditions [19].…”

Section: Resultsmentioning

confidence: 99%

Down‐regulation of heme oxygenase‐2 is associated with the increased expression of heme oxygenase‐1 in human cell lines

Ding¹,

Zhang²,

Furuyama³

et al. 2006

The FEBS Journal

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Heme is an invaluable molecule that is essential for life and is involved in many cellular processes that sense or use oxygen. The intracellular concentration of heme is maintained by the rate of its synthesis and degradation [1]. Many enzymes and their regulators are responsible for heme synthesis [1,2]. On the other hand, heme degradation is mediated by two structurally related isozymes, HO-1 and HO-2, to generate biliverdin IXa, carbon monoxide (CO), and ferrous iron [3]. Biliverdin IXa is immediately reduced to bilirubin IXa. HO-1 has attracted particular attention, because its expression is induced by its substrate, heme, in animals [4,5] and in primary cultures of macrophages [6][7][8][9]. It has therefore provided a good example of substrate-mediated induction of an enzyme in mammals [10,11]. Intracellular heme concentrations are maintained in part by heme degradation, which is catalyzed by heme oxygenase. Heme oxygenase consists of two structurally related isozymes, HO-1 and HO-2. Recent studies have identified HO-2 as a potential oxygen sensor. To gain further insights into the regulatory role of HO-2 in heme homeostasis, we analyzed the expression profiles of HO-2 and the biochemical consequences of HO-2 knockdown with specific short interfering RNA (siRNA) in human cells. Both HO-2 mRNA and protein are expressed in the eight human cancer cell lines examined, and HO-1 expression is detectable in five of the cell lines, including HeLa cervical cancer and HepG2 hepatoma. Down-regulation of HO-2 expression with siRNA against HO-2 (siHO-2) caused induction of HO-1 expression at both mRNA and protein levels in HeLa and HepG2 cells. In contrast, knockdown of HO-1 expression did not noticeably influence HO-2 expression. HO-2 knockdown prolonged the half-life of HO-1 mRNA twofold in HeLa cells. Transient transfection assays in HeLa cells revealed that the 4.5-kb human HO-1 gene promoter was activated with selective knockdown of HO-2 in a sequence-dependent manner. Moreover, HO-2 knockdown caused heme accumulation in HeLa and HepG2 cells only when exposed to exogenous hemin. HO-2 knockdown may mimic a certain physiological change that is important in the maintenance of cellular heme homeostasis. These results suggest that HO-2 may down-regulate the expression of HO-1, thereby directing the co-ordinated expression of HO-1 and HO-2.Abbreviations GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HO, heme oxygenase; MARE, Maf recognition element; SA, succinylacetone; SnPP, Sn-protoporphyrin.

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“…YN‐1 human erythroleukemia cells [27] were maintained in Iscove ’ s modified Dulbecco ’ s medium (Sigma‐Aldrich). K562 human erythroleukemia cells and Jurkat human lymphoblastic cells were maintained in RPMI‐1640 (Wako Pure Chemical Industries).…”

Section: Methodsmentioning

confidence: 99%

Hypoxia decreases the expression of the two enzymes responsible for producing linear and cyclic tetrapyrroles in the heme biosynthetic pathway

et al. 2008

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Heme is synthesized in all cell types in aerobic organisms. Hydroxymethylbilane synthase (HMBS) and uroporphyrinogen III synthase (UROS) catalyze two consecutive reactions in the heme biosynthetic pathway, generating the first linear and the first cyclic tetrapyrroles, respectively. Each of the HMBS and UROS genes contains the two separate promoters that generate ubiquitous and erythroid‐specific mRNAs. Despite the functional significance of HMBS and UROS, regulation of their gene expression remains to be investigated. Here, we showed that hypoxia (1% O2) decreased the expression of ubiquitous mRNAs for HMBS and UROS by three‐ and twofold, respectively, in human hepatic cells (HepG2 and Hep3B), whereas the expression of ubiquitous and erythroid HMBS and UROS mRNAs remained unchanged in erythroid cells (YN‐1 and K562). Unexpectedly, hypoxia did not decrease the half‐life of HMBS mRNA (8.4 h under normoxia versus 9.1 h under hypoxia) or UROS mRNA (9.0 versus 10.4 h) in hepatic cells. It is therefore unlikely that a change in mRNA stability is responsible for the hypoxia‐mediated decrease in the expression levels of these mRNAs. Furthermore, expression levels of HMBS and UROS mRNAs were decreased under normoxia by treatment with deferoxamine or cobalt chloride in hepatic cells, while hypoxia‐inducible factor 1α was accumulated. Thus, the decrease in the expression of ubiquitous HMBS and UROS mRNAs is associated with accumulation of hypoxia‐inducible factor 1α protein. In conclusion, the expression of HMBS and UROS mRNAs may be coordinately regulated, which represents a newly identified mechanism that is important for heme homeostasis.

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Two chronic myelogenous leultaemia cell lines which represent different stages of erythroid differentiation

Cited by 33 publications

References 27 publications

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

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

Down‐regulation of heme oxygenase‐2 is associated with the increased expression of heme oxygenase‐1 in human cell lines

Hypoxia decreases the expression of the two enzymes responsible for producing linear and cyclic tetrapyrroles in the heme biosynthetic pathway

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