|
Originally published In Press as doi:10.1074/jbc.M312948200 on January 26, 2004
J. Biol. Chem., Vol. 279, Issue 15, 14844-14852, April 9, 2004
Homocysteine Increases the Expression of Vascular Endothelial Growth Factor by a Mechanism Involving Endoplasmic Reticulum Stress and Transcription Factor ATF4*
C. Nathaniel Roybal ,
Shujie Yang,
Chiao-Wang Sun ,
Diego Hurtado,
David L. Vander Jagt,
Tim M. Townes, and
Steve F. Abcouwer¶
From the
Department of Biochemistry and Molecular Biology, University of New Mexico School of Medicine, Albuquerque, New Mexico 87131-0001 and the Department of Biochemistry and Molecular Genetics, Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294
Vascular endothelial growth factor (VEGF) plays a key role in the development and progression of diabetic retinopathy. We previously demonstrated that amino acid deprivation and other inducers of endoplasmic reticulum-stress (ER stress) up-regulate the expression of VEGF in the retinal-pigmented epithelial cell line ARPE-19. Because homocysteine causes ER stress, we hypothesized that VEGF expression is increased by ambient homocysteine. DL-Homocysteine-induced VEGF expression was investigated in confluent ARPE-19 cultures. Northern analysis showed that homocysteine increased steady state VEGF mRNA levels 4.4-fold. Other thiol-containing compounds, including L-homocysteine thiolactone and DTT, induced VEGF expression 7.9- and 8.8-fold. Transcriptional run-on assays and mRNA decay studies demonstrated that the increase in VEGF mRNA levels was caused by increased transcription rather than mRNA stabilization. VEGF mRNA induction paralleled that of the ER-stress gene GRP78. Homocysteine treatment caused transient phosphorylation of eIF2 and an increase in ATF4 protein level. Overexpression of a dominant-negative ATF4 abolished the VEGF response to homocysteine treatment and to amino acid deprivation. VEGF mRNA expression by ATF4–/– MEF did not respond to homocysteine treatment and the response was restored with expression of wild-type ATF4. These studies indicate that expression of the pro-angiogenic factor VEGF is increased by homocysteine and other thiol-containing reductive compounds via ATF4-dependent activation of VEGF transcription.
Received for publication, November 27, 2003
, and in revised form, January 25, 2004.
* This work was supported by Grants EY13695 (to D. L. V. J.) and EY014535 (to C. N. R.) from the National Eye Institute and Grant CA72772 (to S. F. A.) from the NCI, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, MSC08-4670, University of New Mexico School of Medicine, Albuquerque, NM 87131-0001. Tel.: 505-272-4138; Fax: 505-272-6587; E-mail: sabcouwer{at}salud.unm.edu.
 CiteULike  Complore  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J.-R. Hsiao, K.-C. Chang, C.-W. Chen, S.-Y. Wu, I.-J. Su, M.-C. Hsu, Y.-T. Jin, S.-T. Tsai, K. Takada, and Y. Chang
Endoplasmic Reticulum Stress Triggers XBP-1-Mediated Up-regulation of an EBV Oncoprotein in Nasopharyngeal Carcinoma
Cancer Res.,
May 15, 2009;
69(10):
4461 - 4467.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. C. States, S. Srivastava, Y. Chen, and A. Barchowsky
Arsenic and Cardiovascular Disease
Toxicol. Sci.,
February 1, 2009;
107(2):
312 - 323.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Inokuchi, Y. Nakajima, M. Shimazawa, T. Kurita, M. Kubo, A. Saito, H. Sajiki, T. Kudo, M. Aihara, K. Imaizumi, et al.
Effect of an Inducer of BiP, a Molecular Chaperone, on Endoplasmic Reticulum (ER) Stress-Induced Retinal Cell Death
Invest. Ophthalmol. Vis. Sci.,
January 1, 2009;
50(1):
334 - 344.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. F. Abcouwer and C. N. Roybal
Regulation of Vascular Endothelial Growth Factor A by Activating Transcription Factor 4
Circ. Res.,
October 24, 2008;
103(9):
e118 - e118.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. M. Khachigian, A. Bobik, P. Kanellakis, and K. Malabanan
Response to Abcouwer and Roybal
Circ. Res.,
October 24, 2008;
103(9):
e119 - e119.
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. P. Malabanan, P. Kanellakis, A. Bobik, and L. M. Khachigian
Activation Transcription Factor-4 Induced by Fibroblast Growth Factor-2 Regulates Vascular Endothelial Growth Factor-A Transcription in Vascular Smooth Muscle Cells and Mediates Intimal Thickening in Rat Arteries Following Balloon Injury
Circ. Res.,
August 15, 2008;
103(4):
378 - 387.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. A. Medina
Hyperhomocysteinemia and Occlusive Vascular Disease: An Emergent Role for Fibroblast Growth Factor 2
Circ. Res.,
April 25, 2008;
102(8):
869 - 870.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Chakraborty, S. Jain, and G. C. Kundu
Osteopontin Promotes Vascular Endothelial Growth Factor Dependent Breast Tumor Growth and Angiogenesis via Autocrine and Paracrine Mechanisms
Cancer Res.,
January 1, 2008;
68(1):
152 - 161.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. J. Carter
EIF2B and Oligodendrocyte Survival: Where Nature and Nurture Meet in Bipolar Disorder and Schizophrenia?
Schizophr Bull,
November 1, 2007;
33(6):
1343 - 1353.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Chwatko, G. H. J. Boers, K. A. Strauss, D. M. Shih, and H. Jakubowski
Mutations in methylenetetrahydrofolate reductase or cystathionine {beta}-syntase gene, or a high-methionine diet, increase homocysteine thiolactone levels in humans and mice
FASEB J,
June 1, 2007;
21(8):
1707 - 1713.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. S. Colombo, G. Menicucci, P. G. McGuire, and A. Das
Hepatocyte Growth Factor/Scatter Factor Promotes Retinal Angiogenesis through Increased Urokinase Expression
Invest. Ophthalmol. Vis. Sci.,
April 1, 2007;
48(4):
1793 - 1800.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Zimny, M. Sikora, A. Guranowski, and H. Jakubowski
Protective Mechanisms against Homocysteine Toxicity: THE ROLE OF BLEOMYCIN HYDROLASE
J. Biol. Chem.,
August 11, 2006;
281(32):
22485 - 22492.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Jakubowski
Pathophysiological Consequences of Homocysteine Excess
J. Nutr.,
June 1, 2006;
136(6):
1741S - 1749S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. N. Roybal, L. Y. Marmorstein, D. L. Vander Jagt, and S. F. Abcouwer
Aberrant Accumulation of Fibulin-3 in the Endoplasmic Reticulum Leads to Activation of the Unfolded Protein Response and VEGF Expression
Invest. Ophthalmol. Vis. Sci.,
November 1, 2005;
46(11):
3973 - 3979.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. N. Roybal, L. A. Hunsaker, O. Barbash, D. L. V. Jagt, and S. F. Abcouwer
The Oxidative Stressor Arsenite Activates Vascular Endothelial Growth Factor mRNA Transcription by an ATF4-dependent Mechanism
J. Biol. Chem.,
May 27, 2005;
280(21):
20331 - 20339.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Hong, M.-y. Lin, J.-m. Huang, P. Baumeister, S. Hakre, A. L. Roy, and A. S. Lee
Transcriptional Regulation of the Grp78 Promoter by Endoplasmic Reticulum Stress: ROLE OF TFII-I AND ITS TYROSINE PHOSPHORYLATION
J. Biol. Chem.,
April 29, 2005;
280(17):
16821 - 16828.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Seznec, D. Simon, C. Bouton, L. Reutenauer, A. Hertzog, P. Golik, V. Procaccio, M. Patel, J.-C. Drapier, M. Koenig, et al.
Friedreich ataxia: the oxidative stress paradox
Hum. Mol. Genet.,
February 15, 2005;
14(4):
463 - 474.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. V. Bobrovnikova-Marjon, P. L. Marjon, O. Barbash, D. L. Vander Jagt, and S. F. Abcouwer
Expression of Angiogenic Factors Vascular Endothelial Growth Factor and Interleukin-8/CXCL8 Is Highly Responsive to Ambient Glutamine Availability: Role of Nuclear Factor-{kappa}B and Activating Protein-1
Cancer Res.,
July 15, 2004;
64(14):
4858 - 4869.
[Abstract]
[Full Text]
[PDF]
|
|
|
Copyright © 2004 by the American Society for Biochemistry and Molecular Biology.
|
Advertisement
Advertisement
|
