Heme-regulated eIF2α kinase modifies the phenotypic severity of murine models of erythropoietic protoporphyria and β-thalassemia

被引:75
作者
Han, AP
Fleming, MD
Chen, JJ
机构
[1] Harvard Univ, MIT, Div Hlth Sci & Technol, Cambridge, MA 02139 USA
[2] Harvard Univ, Sch Med, Dept Pathol, Childrens Hosp, Cambridge, MA 02138 USA
关键词
D O I
10.1172/JCI24141
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Heme-regulated eIF2 alpha kinase (HRI) controls protein synthesis by phosphorylating the alpha-subunit of eukaryotic translational initiation factor 2 (eIF2 alpha.). In heme deficiency, HRI is essential for translational regulation of alpha- and beta-globins and for the survival of erythroid progenitors. HRI is also activated by a number of cytoplasmic stresses other than heme deficiency, including oxidative stress and heat shock. However, to date, HRI has not been implicated in the pathogenesis of any known human disease or mouse phenotype. Here we report the essential role of HRI in 2 mouse models of human rbc disorders, namely erythropoietic protoporphyria (EPP) and beta-thalassemia. In both cases, lack of HRI adversely modifies the phenotype: HRI deficiency exacerbates EPP and renders beta-thalassemia embryonically lethal. This study establishes the protective function of HRI in inherited rbc diseases in mice and suggests that HRI may be a significant modifier of many rbc disorders in humans. Our findings also demonstrate that translational regulation could play a critical role in the clinical manifestation of rbc diseases.
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页码:1562 / 1570
页数:9
相关论文
共 44 条
[1]   Characterization of transgenic mice with targeted disruption of the catalytic domain of the double-stranded RNA-dependent protein kinase, PKR [J].
Abraham, N ;
Stojdl, DF ;
Duncan, PI ;
Méthot, N ;
Ishii, T ;
Dubé, M ;
Vanderhyden, BC ;
Atkins, HL ;
Gray, DA ;
McBurney, MW ;
Koromilas, AE ;
Brown, EG ;
Sonenberg, N ;
Bell, JC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (09) :5953-5962
[2]  
BASSET P, 1978, BLOOD, V51, P971
[3]   Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2α kinase [J].
Bauer, BN ;
Rafie-Kolpin, M ;
Lu, LR ;
Han, AP ;
Chen, JJ .
BIOCHEMISTRY, 2001, 40 (38) :11543-11551
[4]   Characterization of the hemin-sensitive eukaryotic initiation factor 2α kinase from mouse nonerythroid cells [J].
Berlanga, JJ ;
Herrero, S ;
de Haro, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (48) :32340-32346
[5]   Characterization of a mammalian homolog of the GCN2 eukaryotic initiation factor 2α kinase [J].
Berlanga, JJ ;
Santoyo, J ;
de Haro, C .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1999, 265 (02) :754-762
[6]  
Centis F, 2000, BLOOD, V96, P3624
[7]   Heme-regulated eIF-2α kinase purifies as a hemoprotein [J].
Chefalo, PJ ;
Oh, JH ;
Rafie-Kolpin, M ;
Kan, B ;
Chen, JJ .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1998, 258 (02) :820-830
[8]  
Chen JJ, 2000, COLD SPRING HARBOR M, V39, P529
[9]   CLONING OF THE CDNA OF THE HEME-REGULATED EUKARYOTIC INITIATION FACTOR-2-ALPHA (EIF-2-ALPHA) KINASE OF RABBIT RETICULOCYTES - HOMOLOGY TO YEAST GCN2 PROTEIN-KINASE AND HUMAN DOUBLE-STRANDED-RNA-DEPENDENT EIF-2-ALPHA KINASE [J].
CHEN, JJ ;
THROOP, MS ;
GEHRKE, L ;
KUO, I ;
PAL, JK ;
BRODSKY, M ;
LONDON, IM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1991, 88 (17) :7729-7733
[10]   HUMAN P68 KINASE EXHIBITS GROWTH SUPPRESSION IN YEAST AND HOMOLOGY TO THE TRANSLATIONAL REGULATOR GCN2 [J].
CHONG, KL ;
FENG, L ;
SCHAPPERT, K ;
MEURS, E ;
DONAHUE, TF ;
FRIESEN, JD ;
HOVANESSIAN, AG ;
WILLIAMS, BRG .
EMBO JOURNAL, 1992, 11 (04) :1553-1562