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

FEBS Journal - Tập 275 Số 23 - Trang 5947-5959 - 2008
Patrick D. Vargas1, Kazumichi Furuyama1, Shigeru Sassa2, Shigeki Shibahara1
1Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Miyagi, Japan.
2 Laboratory of Biochemical Hematology, Rockefeller University, New York, NY, USA

Tóm tắt

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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Tài liệu tham khảo

10.1620/tjem.213.1

10.3164/jcbn.38.138

10.1038/285017a0

10.1039/p19800001283

10.1073/pnas.85.19.7049

10.1007/BF02110033

10.1042/bj2320151

10.1016/S0021-9258(18)64792-1

10.1016/0014-5793(69)80142-0

10.1016/0020-711X(80)90159-7

10.1016/0005-2744(71)90178-1

10.1111/j.1749-6632.1975.tb41545.x

10.1016/0014-5793(80)80134-7

10.1016/0888-7543(90)90030-X

10.1073/pnas.85.1.6

10.1111/j.1432-1033.1987.tb10548.x

Anderson KE, 2001, The Metabolic and Molecular Bases of Inherited Disease, 2991

10.1007/BF01213085

10.1073/pnas.63.3.856

10.1126/science.161.3844.907

10.1074/jbc.275.4.2295

10.1006/geno.2000.6373

10.1093/jb/mvh111

10.1016/j.febslet.2007.06.018

10.1159/000104457

10.1111/j.1742-4658.2006.05319.x

10.1111/j.1365-2141.1993.tb03205.x

10.1006/bbrc.1998.8131

10.1016/S0021-9258(19)51104-8

10.1073/pnas.82.16.5328

10.1016/S0955-0674(00)00194-0

10.1016/S0021-9258(18)81783-5

10.1016/S0009-8981(03)00276-6

10.1172/JCI31370

Mazure NM, 2002, Repression of alpha‐fetoprotein gene expression under hypoxic conditions in human hepatoma cells: characterization of a negative hypoxia response element that mediates opposite effects of hypoxia inducible factor‐1 and c‐Myc, Cancer Res, 62, 1158

10.1093/nar/gki839

10.1128/MCB.23.24.9361-9374.2003

10.1074/jbc.M706861200

10.1046/j.1365-2958.2003.03589.x

10.1136/bmj.286.6375.1408

10.1136/bmj.286.6373.1269

10.1111/j.1365-2141.2005.05617.x

10.1016/j.blre.2004.08.001

10.1001/jama.295.19.2251

10.1016/S0140-6736(06)68339-6

10.1016/S0140-6736(00)04645-6

10.1016/S0140-6736(00)03165-2

10.1172/JCI6816

10.1046/j.1471-4159.1997.68020726.x

10.1016/S0021-9258(19)85981-1

Sambrook J, 2001, Molecular Cloning: A Laboratory Manual

10.1016/0378-1119(91)90434-D

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FEBS Journal

Tập 275 Số 23

5947-5959

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