A 40-bp RNA element that mediates stabilization of vascular endothelial growth factor mRNA by HuR

被引:106
作者
Goldberg-Cohen, I
Furneauxb, H
Levy, AP
机构
[1] Technion Israel Inst Technol, Bruce Rappaport Fac Med, IL-31096 Haifa, Israel
[2] Univ Connecticut, Ctr Hlth, Dept Physiol, Farmington, CT 06032 USA
关键词
D O I
10.1074/jbc.M108703200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
VEGF is a critical mediator of hypoxia-induced angiogenesis in numerous physiological and pathophysiological conditions. The hypoxic induction of VEGF is due in large part to an increase in the stability of its mRNA. We recently demonstrated that the stabilization of VEGF mRNA by hypoxia is dependent upon the RNA-binding protein HuR. This report describes the identification of a 40-bp functional HuR binding site in the VEGF mRNA 3'-untranslated region. This element can confer HuR-mediated stabilization of a heterologous gene in vitro and in vivo. Furthermore, the element is sufficient to confer an increase in the hypoxic induction of a heterologous gene. Deletion of the HuR binding site within this 40-bp element as mapped by RNase T1 and lead footprinting uncouples a stabilizing sequence from a destabilizing sequence, thus providing a novel RNA-protein regulatory model that might be exploited to manipulate VEGF expression and hypoxia-induced angiogenesis.
引用
收藏
页码:13635 / 13640
页数:6
相关论文
共 32 条
[1]   VASCULAR ENDOTHELIAL GROWTH-FACTOR IN OCULAR FLUID OF PATIENTS WITH DIABETIC-RETINOPATHY AND OTHER RETINAL DISORDERS [J].
AIELLO, LP ;
AVERY, RL ;
ARRIGG, PG ;
KEYT, BA ;
JAMPEL, HD ;
SHAH, ST ;
PASQUALE, LR ;
THIEME, H ;
IWAMOTO, MA ;
PARK, JE ;
NGUYEN, HV ;
AIELLO, LM ;
FERRARA, N ;
KING, GL .
NEW ENGLAND JOURNAL OF MEDICINE, 1994, 331 (22) :1480-1487
[2]   Characterization of physiologically regulated vectors for the treatment of ischemic disease [J].
Boast, K ;
Binley, K ;
Iqball, S ;
Price, T ;
Spearman, H ;
Kingsman, S ;
Kingsman, A ;
Naylor, S .
HUMAN GENE THERAPY, 1999, 10 (13) :2197-2208
[3]   Identification of a human VPF/VEGF 3′ untranslated region mediating hypoxia-induced mRNA stability [J].
Claffey, KP ;
Shih, SC ;
Mullen, A ;
Dziennis, S ;
Cusick, JL ;
Abrams, KR ;
Lee, SW ;
Detmar, M .
MOLECULAR BIOLOGY OF THE CELL, 1998, 9 (02) :469-481
[4]   HNS, a nuclear-cytoplasmic shuttling sequence in HuR [J].
Fan, XHC ;
Steitz, JA .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1998, 95 (26) :15293-15298
[5]   Overexpression of HuR, a nuclear-cytoplasmic shuttling protein, increases the in vivo stability of ARE-containing mRNAs [J].
Fan, XHC ;
Steitz, JA .
EMBO JOURNAL, 1998, 17 (12) :3448-3460
[6]   ELAV proteins stabilize deadenylated intermediates in a novel in vitro mRNA deadenylation/degradation system [J].
Ford, LP ;
Watson, J ;
Keene, JD ;
Wilusz, J .
GENES & DEVELOPMENT, 1999, 13 (02) :188-201
[7]   The macrophage - a novel system to deliver gene therapy to pathological hypoxia [J].
Griffiths, L ;
Binley, K ;
Iqball, S ;
Kan, O ;
Maxwell, P ;
Ratcliffe, P ;
Lewis, C ;
Harris, A ;
Kingsman, S ;
Naylor, S .
GENE THERAPY, 2000, 7 (03) :255-262
[8]   Tumor antigen HuR binds specifically to one of five protein-binding segments in the 3′-untranslated region of the neurofibromin messenger RNA [J].
Haeussler, J ;
Haeusler, J ;
Striebel, AM ;
Assum, G ;
Vogel, W ;
Furneaux, H ;
Krone, W .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2000, 267 (03) :726-732
[9]   p21waf1 mRNA contains a conserved element in its 3′-untranslated region that is bound by the Elav-like mRNA-stabilizing proteins [J].
Joseph, B ;
Orlian, M ;
Furneaux, H .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (32) :20511-20516
[10]  
Koshikawa N, 2000, CANCER RES, V60, P2936