TY - JOUR
T1 - A prolyl-hydroxylase inhibitor, ethyl-3,4-dihydroxybenzoate, induces haem oxygenase-1 expression in human cells through a mechanism independent of hypoxia-inducible factor-1α
AU - Li, Bin
AU - Takeda, Kazuhisa
AU - Yokoyama, Satoru
AU - Shibahara, Shigeki
N1 - Funding Information:
Grant-in-Aid for Scientific Research on Priority Areas; 21st Century COE Program Special Research Grant ‘the Center for Innovative Therapeutic Development for Common Diseases’ from the Ministry of Education, Science, Sports, and Culture of Japan; Cosmetology Foundation.
PY - 2008/11
Y1 - 2008/11
N2 - Hypoxia-inducible factor (HIF)-1 is important for cellular homeostasis under hypoxia. Expression of haem oxygenase-1 (HO-1), an essential enzyme in haem catabolism, varies under hypoxia, depending on cell types. Here, we studied the role of HIF-1α, a component of HIF-1, in the regulation of HO-1 expression using three human cell lines: HeLa cervical cancer, and ARPE-19 and D407 retinal pigment epithelial cells. Under hypoxia (1% O2), the expression of HO-1 mRNA was decreased in HeLa cells, increased in D407 cells, and unchanged in ARPE-19 cells, while HIF-1α protein was accumulated in these cell lines. Thus, HIF-1α is unlikely to function as a key regulator for HO-1 expression under hypoxia. We then used ethyl-3,4-dihydroxybenzoate (EDHB), an inhibitor of prolyl hydroxylases, to accumulate HIF-1α protein under normoxia. Treatment with EDHB (250-500 μM) increased HIF-1α protein levels in HeLa and D407 cells, but not in ARPE-19 cells, whereas EDHB at lower concentrations (50-100 μM) consistently induced HO-1 mRNA expression (about 20-fold) in these three cell lines. Moreover, EDHB increased the HO-1 gene promoter activity via the enhancer that lacks a HIF-1-binding site. In conclusion, the signals evoked by hypoxia and after EDHB treatment differentially regulate HO-1 mRNA expression through HIF-1α-independent mechanisms.
AB - Hypoxia-inducible factor (HIF)-1 is important for cellular homeostasis under hypoxia. Expression of haem oxygenase-1 (HO-1), an essential enzyme in haem catabolism, varies under hypoxia, depending on cell types. Here, we studied the role of HIF-1α, a component of HIF-1, in the regulation of HO-1 expression using three human cell lines: HeLa cervical cancer, and ARPE-19 and D407 retinal pigment epithelial cells. Under hypoxia (1% O2), the expression of HO-1 mRNA was decreased in HeLa cells, increased in D407 cells, and unchanged in ARPE-19 cells, while HIF-1α protein was accumulated in these cell lines. Thus, HIF-1α is unlikely to function as a key regulator for HO-1 expression under hypoxia. We then used ethyl-3,4-dihydroxybenzoate (EDHB), an inhibitor of prolyl hydroxylases, to accumulate HIF-1α protein under normoxia. Treatment with EDHB (250-500 μM) increased HIF-1α protein levels in HeLa and D407 cells, but not in ARPE-19 cells, whereas EDHB at lower concentrations (50-100 μM) consistently induced HO-1 mRNA expression (about 20-fold) in these three cell lines. Moreover, EDHB increased the HO-1 gene promoter activity via the enhancer that lacks a HIF-1-binding site. In conclusion, the signals evoked by hypoxia and after EDHB treatment differentially regulate HO-1 mRNA expression through HIF-1α-independent mechanisms.
KW - Ethyl-3,4-dihydroxybenzoate
KW - Haem oxygenase-1
KW - Hypoxia
KW - Hypoxia-inducible factor-1α
KW - Prolyl-hydroxylase inhibitor
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U2 - 10.1093/jb/mvn115
DO - 10.1093/jb/mvn115
M3 - Article
C2 - 18799519
AN - SCOPUS:55349132388
VL - 144
SP - 643
EP - 654
JO - Journal of Biochemistry
JF - Journal of Biochemistry
SN - 0021-924X
IS - 5
ER -