Tumor necrosis factor-α causes accumulation of a ubiquitinated form of hypoxia inducible factor-1α through a nuclear factor-κB-dependent pathway

被引:143
作者
Zhou, J [1 ]
Schmid, T [1 ]
Brüne, B [1 ]
机构
[1] Univ Kaiserslautern, Dept Cell Biol, Fac Biol, D-67663 Kaiserslautern, Germany
关键词
D O I
10.1091/mbc.E02-09-0598
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Hypoxia-inducible factor-1 (HIF-1) is a regulator of metabolic adaptation to hypoxia. It is, now appreciated that HIF-1alpha accumulation is achieved under normoxic conditions by various factors, such as TNF-alpha. Here, it was our intention to gain insight into the signaling mechanisms used by TNF-alpha to stimulate HIF-1alpha. In tubular LLC-PK1 or human embryonic kidney cells, TNF-alpha induced accumulation of HIF-1alpha, protein but not HIF-1alpha mRNA. Blocking nuclear factor (NF)kappaB with sulfasalazine or expression of an IkappaB superrepressor attenuated HIF-1alpha accumulation, whereas transfection of active p50/p65-NF-kappaB subunits mimicked a TNF-alpha response. Experiments with actinomycin D and cycloheximide also pointed to a transcriptional and translational process in facilitating the TNF-alpha, response. Interestingly, and in contrast to established hypoxic signaling concepts, TNF-alpha elicited HIF-1alpha accumulation in a ubiquitinated form that still bound the von Hippel-Lindau (pVHL) protein. These data indicate that HIF-1alpha accumulation by TNF-alpha demands the NF-kappaB pathway, preserves ubiquitination of HIF-1alpha, and allows the HIF-1alpha-pVHL interaction.
引用
收藏
页码:2216 / 2225
页数:10
相关论文
共 35 条
[1]   HIF-1 expression in healing wounds:: HIF-1α induction in primary inflammatory cells by TNF-α [J].
Albina, JE ;
Mastrofrancesco, B ;
Vessella, JA ;
Louis, CA ;
Henry, WL ;
Reichner, JS .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 2001, 281 (06) :C1971-C1977
[2]   Lack of evidence for the involvement of the phosphoinositide 3-kinase/Akt pathway in the activation of hypoxia-inducible factors by low oxygen tension [J].
Alvarez-Tejado, M ;
Alfranca, A ;
Aragonés, J ;
Vara, A ;
Landázuri, MO ;
del Peso, L .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (16) :13508-13517
[3]   Phosphatidylinositol 3-kinase/Akt signaling is neither required for hypoxic stabilization of HIF-1α nor sufficient for HIF-1-dependent target gene transcription [J].
Arsham, AM ;
Plas, DR ;
Thompson, CB ;
Simon, MC .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (17) :15162-15170
[4]   Signal transduction by tumor necrosis factor and its relatives [J].
Baud, V ;
Karin, M .
TRENDS IN CELL BIOLOGY, 2001, 11 (09) :372-377
[5]   Role of prolyl hydroxylation in oncogenically stabilized hypoxia-inducible factor-1α [J].
Chan, DA ;
Sutphin, PD ;
Denko, NC ;
Giaccia, AJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2002, 277 (42) :40112-40117
[6]   Hypoxia and interleukin-1β stimulate vascular endothelial growth factor production in human proximal tubular cells [J].
El Awad, B ;
Kreft, B ;
Wolber, EM ;
Hellwig-Bürgel, T ;
Metzen, E ;
Fandrey, J ;
Jelkmann, W .
KIDNEY INTERNATIONAL, 2000, 58 (01) :43-50
[7]   Thrombin activates the hypoxia-inducible factor-1 signaling pathway in vascular smooth muscle cells role of the p22phox-containing NADPH oxidase [J].
Görlach, A ;
Diebold, I ;
Schini-Kerth, VB ;
Berchner-Pfannschmidt, U ;
Roth, U ;
Brandes, RP ;
Kietzmann, T ;
Busse, R .
CIRCULATION RESEARCH, 2001, 89 (01) :47-54
[8]   A non-hypoxic, ROS-sensitive pathway mediates TNF-α-dependent regulation of HIF-1α [J].
Haddad, JJ ;
Land, SC .
FEBS LETTERS, 2001, 505 (02) :269-274
[9]   Interleukin-1β and tumor necrosis factor-α stimulate DNA binding of hypoxia-inducible factor-1 [J].
Hellwig-Bürgel, T ;
Rutkowski, K ;
Metzen, E ;
Fandrey, J ;
Jelkmann, W .
BLOOD, 1999, 94 (05) :1561-1567
[10]   Mitogen-activated protein kinase kinase inhibitor PD98059 blocks the trans-activation but not the stabilization or DNA binding ability of hypoxia-inducible factor-1α [J].
Hur, E ;
Chang, KY ;
Lee, E ;
Lee, SK ;
Park, H .
MOLECULAR PHARMACOLOGY, 2001, 59 (05) :1216-1224