Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation Research
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation Research. 2005;96:1145-1151
Published online before print May 5, 2005, doi: 10.1161/01.RES.0000168802.43528.e1
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
96/11/1145    most recent
01.RES.0000168802.43528.e1v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Pi, X.
Right arrow Articles by Berk, B. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pi, X.
Right arrow Articles by Berk, B. C.
Related Collections
Right arrow Endothelium/vascular type/nitric oxide
Right arrow Angiogenesis
Right arrow Cell signalling/signal transduction
Right arrow Gene regulation
Right arrow Ischemic biology - basic studies
(Circulation Research. 2005;96:1145.)
© 2005 American Heart Association, Inc.

Molecular Medicine

BMK1/ERK5 Is a Novel Regulator of Angiogenesis by Destabilizing Hypoxia Inducible Factor 1{alpha}

Xinchun Pi, Gwenaele Garin, Liang Xie, Qinlei Zheng, Heng Wei, Jun-ichi Abe, Chen Yan, Bradford C. Berk

From the Cardiovascular Research Institute and Departments of Medicine (X.P., G.G., Q.Z., H.W., J.A., C.Y., B.C.B.) and Pharmacology (L.X.), University of Rochester, NY

Correspondence to Dr Bradford C. Berk, Cardiology Unit, Box 679, 601 Elmwood Ave, Rochester, NY 14642. E-mail Bradford_Berk{at}urmc.rochester.edu

Big MAP kinase 1 (BMK1 or ERK5) is a key mediator of endothelial cell (EC) function as shown by impaired embryonic angiogenesis and vascular collapse in BMK1 knockout mice. Hypoxia inducible factor 1{alpha} (HIF1{alpha}), a potent mediator of angiogenesis, is positively regulated by the MAP kinases, ERK1/2. Because BMK1 deficiency is associated with impaired angiogenesis we hypothesized that BMK1 might regulate HIF1{alpha}. To test this hypothesis, bovine lung microvascular ECs (BLMECs) were transfected with HIF1{alpha} and BMK1 cDNAs, and stimulated by hypoxia. HIF1{alpha} activity was measured by a reporter gene assay in which luciferase expression was driven by HIF1{alpha} activation. Hypoxia (1% O2, 24 hours) stimulated HIF1{alpha} activity by 5.1±0.6 fold. In the presence of dominant negative (DN)-BMK1, which inhibited BMK1 activity, hypoxia induced HIF1{alpha} activity was enhanced significantly to 6.4±0.4 fold. BMK1 activation by constitutively active (CA)-MEK5 inhibited HIF1{alpha} activity by 46±4%, suggesting BMK1 functions as a negative regulator of HIF1{alpha} activation. Activation of BMK1 reduced HIF1{alpha} protein levels. Ubiquitination inhibitors (30 µmol/L ALLN, 2 µmol/L lactacystin, or 100 nmol/L MG132) reduced the BMK1-mediated effect on HIF1{alpha} expression by >80%, suggesting that BMK1 stimulated HIF1{alpha} proteolysis. The negative effect of BMK1 on HIF1{alpha} was functionally important because transfection with CA-MEK5 significantly decreased EC migration by 68±10%, and inhibited angiogenesis (in vitro Matrigel assay) by 76±7%. In summary, BMK1 is a novel negative regulator of HIF1{alpha} and angiogenesis by increasing HIF1{alpha} ubiquitination and inhibiting HIF1{alpha} activity in endothelial cells.


Key Words: big MAP kinase 1 • hypoxia inducible factor 1{alpha} • angiogenesis




This article has been cited by other articles:


Home page
 J. Biol. Chem.Home page
C. H. Ha, W. Wang, B. S. Jhun, C. Wong, A. Hausser, K. Pfizenmaier, T. A. McKinsey, E. N. Olson, and Z.-G. Jin
Protein Kinase D-dependent Phosphorylation and Nuclear Export of Histone Deacetylase 5 Mediates Vascular Endothelial Growth Factor-induced Gene Expression and Angiogenesis
J. Biol. Chem., May 23, 2008; 283(21): 14590 - 14599.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Biol.Home page
X. Pi, R. Ren, R. Kelley, C. Zhang, M. Moser, A. B. Bohil, M. DiVito, R. E. Cheney, and C. Patterson
Sequential roles for myosin-X in BMP6-dependent filopodial extension, migration, and activation of BMP receptors
J. Cell Biol., December 31, 2007; 179(7): 1569 - 1582.
[Abstract] [Full Text] [PDF]

Home page
 Eukaryot CellHome page
A. W. Truman, S. H. Millson, J. M. Nuttall, V. King, M. Mollapour, C. Prodromou, L. H. Pearl, and P. W. Piper
Expressed in the Yeast Saccharomyces cerevisiae, Human ERK5 Is a Client of the Hsp90 Chaperone That Complements Loss of the Slt2p (Mpk1p) Cell Integrity Stress-Activated Protein Kinase
Eukaryot. Cell, November 1, 2006; 5(11): 1914 - 1924.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
R. E. Schweppe, T. H. Cheung, and N. G. Ahn
Global Gene Expression Analysis of ERK5 and ERK1/2 Signaling Reveals a Role for HIF-1 in ERK5-mediated Responses
J. Biol. Chem., July 28, 2006; 281(30): 20993 - 21003.
[Abstract] [Full Text] [PDF]


Circulation Research Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2005 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.