Nitric oxide inhibits the degradation of IRP2

被引:31
|
作者
Wang, J
Chen, GH
Pantopoulos, K
机构
[1] Sir Mortimer B Davis Jewish Hosp, Lady Davis Inst Med Res, Montreal, PQ H3T 1E2, Canada
[2] McGill Univ, Dept Med, Montreal, PQ H3A 2T5, Canada
关键词
D O I
10.1128/MCB.25.4.1347-1353.2005
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
Iron-regulatory protein 2 (IRP2), a posttranscriptional regulator of iron metabolism, undergoes proteasomal degradation in iron-replete cells, while it is stabilized in iron deficiency or hypoxia. IRP2 also responds to nitric oxide (NO), as shown in various cell types exposed to pharmacological NO donors and in gamma interferon/lipopolysaccharide-stimulated macrophages. However, the diverse experimental systems have yielded conflicting results on whether NO activates or inhibits IRP2. We show here that a treatment of mouse B6 fibroblasts or human H1299 lung cancer cells with the NO-releasing drug S-nitroso-N-acetyl-penicillamine (SNAP) activates IRP2 expression. Moreover, the exposure of H1299 cells to SNAP leads to stabilization of hemagglutinin (HA)-tagged IRP2, with kinetics analogous to those elicited by the iron chelator desferrioxamine. Similar results were obtained with IRP2,,,, a mutant lacking a conserved, IRP2-specific proline- and cysteine-rich domain. Importantly, SNAP fails to stabilize HA-tagged p53, suggesting that under the above experimental conditions, NO does not impair the capacity of the proteasome for protein degradation. Finally, by employing a coculture system of B6 and H1299 cells expressing NO synthase II or IRP2-HA cDNAs, respectively, we demonstrate that NO generated in B6 cells stabilizes IRP2-HA in target H1299 cells by passive diffusion. Thus, biologically synthesized NO promotes IRP2 stabilization without compromising the overall proteasomal activity. These results are consistent with the idea that NO may negatively affect the labile iron pool and thereby trigger responses to iron deficiency.
引用
收藏
页码:1347 / 1353
页数:7
相关论文
共 50 条
  • [21] Converse modulation of IRP1 and IRP2 by immunological stimuli in murine RAW 264.7 macrophages
    Bouton, C
    Oliveira, L
    Drapier, JC
    JOURNAL OF BIOLOGICAL CHEMISTRY, 1998, 273 (16) : 9403 - 9408
  • [22] THE IRON METABOLISM PROTEIN IRP2 IS OVER EXPRESSED IN COLORECTAL ADENOCARCINOMA
    Evans, Sarah
    Bedford, Matthew
    Horniblow, Richard
    Lal, Neeraj
    Beggs, Andrew
    Iqbal, Tariq
    Tucker, Olga
    Tselepis, Chris
    AMERICAN JOURNAL OF HEMATOLOGY, 2016, 91 (03) : E194 - E194
  • [23] Mdm2 is a target and mediator of IRP2 in cell growth control
    Zhang, Jin
    Kong, Xiangmudong
    Zhang, Yanhong
    Sun, Wenqiang
    Xu, Enshun
    Chen, Xinbin
    FASEB JOURNAL, 2020, 34 (02): : 2301 - 2311
  • [24] On the mechanism of iron sensing by IRP2: new players, new paradigms
    Naoko Takahashi-Makise
    Diane McVey Ward
    Jerry Kaplan
    Nature Chemical Biology, 2009, 5 : 874 - 875
  • [25] On the mechanism of iron sensing by IRP2: new players, new paradigms
    Takahashi-Makise, Naoko
    Ward, Diane McVey
    Kaplan, Jerry
    NATURE CHEMICAL BIOLOGY, 2009, 5 (12) : 874 - 875
  • [26] PREPARATION AND CHARACTERIZATION OF PLATINUM METAL PHOSPHIDES RUP2 AND IRP2
    KANER, R
    CASTRO, CA
    GRUSKA, RP
    WOLD, A
    MATERIALS RESEARCH BULLETIN, 1977, 12 (12) : 1143 - 1147
  • [27] Identification of the ubiquitin-protein ligase that recognizes oxidized IRP2
    Yamanaka, K
    Ishikawa, H
    Megumi, Y
    Tokunaga, F
    Kanie, M
    Rouault, TA
    Morishima, I
    Minato, N
    Ishimori, K
    Iwai, K
    NATURE CELL BIOLOGY, 2003, 5 (04) : 336 - 340
  • [28] Nitric oxide inhibits TNF alpha-induced degradation of BCL-2
    Dimmeler, S
    Haendeler, J
    Zeiher, AM
    FASEB JOURNAL, 1997, 11 (03): : 1843 - 1843
  • [29] Stimulation of Hepatic Ferritinophagy Mitigates Irp2 Depletion-Induced Anemia
    Liu, Yutong
    Li, Yuxuan
    Yang, Liu
    Shen, Jiaqi
    Zhao, Hongting
    Dong, Weichen
    Chang, Yanzhong
    Qiao, Tong
    Li, Kuanyu
    ANTIOXIDANTS, 2023, 12 (03)
  • [30] Identification of a heme sensing domain in iron-regulatory protein 2(IRP2)
    Jeong, JS
    Roualt, T
    Levine, R
    FREE RADICAL BIOLOGY AND MEDICINE, 2004, 37 : S109 - S109