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J Biol Chem, Vol. 273, Issue 30, 19294-19303, July 24, 1998
From the ** Beetham Eye Institute and Kinase domain receptor (KDR) is a
high affinity, endothelial cell-specific, autophosphorylating tyrosine
kinase receptor for vascular endothelial growth factor. This
transcriptionally regulated receptor is a critical mediator of
endothelial cell (EC) growth and vascular development. In this study,
we identify a DNA element modulating KDR promoter activity and evaluate
the nuclear binding proteins accounting for a portion of the cell-type
specificity of the region. KDR promoter luciferase activity was
retained within These data illustrate that Sp1 and Sp3 modulate KDR promoter activity
through a novel recognition binding sequence. However, since
Sp1-mediated promoter activation is attenuated by Sp3, endothelial selective KDR promoter activity may be partially regulated by variations in the Sp1/Sp3 ratio.
Transcription Factors Sp1 and Sp3 Alter Vascular Endothelial
Growth Factor Receptor Expression through a Novel Recognition
Sequence
,,,
, and**
Research
Division, Joslin Diabetes Center, Boston, Massachusetts 02215, the
Department of Ophthalmology, Harvard
Medical School, Boston, Massachusetts 02215, and Hybridon,
Inc., Cambridge, Massachusetts 02139
85/+296 and was 10-30-fold higher in EC than non-EC.
Electrophoretic mobility shift assays demonstrated specific nuclear
protein binding to 85/64, and single point mutations suggested
important binding nucleotides between 79/68 with five critical
bases between 74/70 (5'-CTCCT-3'). DNA-protein complexes were
displaced by Sp1 consensus sequence oligodeoxynucleotides and
supershifted by Sp1- and Sp3-specific antibodies. Sp1 and Sp3 protein
in EC nuclear extracts bound the 79/68 region even when all
surrounding classic Sp1 recognition sites were removed. Sp1 protein in
nuclear extracts was 4-24-fold higher in EC than non-EC, whereas Sp3
was 3-7-fold higher. Sp1/Sp3 ratios in EC were 2-10-fold higher.
Overexpression of Sp1 protein increased KDR promoter activity 3-fold in
both EC and non-EC, whereas simultaneous co-expression of Sp3
attenuated this response. An Sp1 consensus sequence cis
element "decoy" reduced EC KDR promoter activity and mRNA
expression by 85 and 69%, respectively. An antisense phosphorothioate
oligodeoxynucleotide to Sp1 inhibited Sp1 and KDR protein expression by
66 and 68%, respectively, without changing Sp3 protein expression.
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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G. Krikun, F. Schatz, N. Mackman, S. Guller, R. Demopoulos, and C. J. Lockwood Regulation of Tissue Factor Gene Expression In Human Endometrium by Transcription Factors Sp1 and Sp3 Mol. Endocrinol., March 1, 2000; 14(3): 393 - 400. [Abstract] [Full Text]
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T. Santalucia, K. R. Boheler, N. J. Brand, U. Sahye, C. Fandos, F. Vinals, J. Ferre, X. Testar, M. Palacin, and A. Zorzano Factors Involved in GLUT-1 Glucose Transporter Gene Transcription in Cardiac Muscle J. Biol. Chem., June 18, 1999; 274(25): 17626 - 17634. [Abstract] [Full Text] [PDF]
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S. Ammanamanchi and M. G. Brattain Sp3 Is a Transcriptional Repressor of Transforming Growth Factor-beta Receptors J. Biol. Chem., January 26, 2001; 276(5): 3348 - 3352. [Abstract] [Full Text] [PDF]
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Q. Xu, Y.-S. Ji, and J. F. Schmedtje Jr. Sp1 Increases Expression of Cyclooxygenase-2 in Hypoxic Vascular Endothelium. IMPLICATIONS FOR THE MECHANISMS OF AORTIC ANEURYSM AND HEART FAILURE J. Biol. Chem., August 4, 2000; 275(32): 24583 - 24589. [Abstract] [Full Text] [PDF]
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C. H. Wendt, G. Gick, R. Sharma, Y. Zhuang, W. Deng, and D. H. Ingbar Up-regulation of Na,K-ATPase beta 1 Transcription by Hyperoxia Is Mediated by SP1/SP3 Binding J. Biol. Chem., December 22, 2000; 275(52): 41396 - 41404. [Abstract] [Full Text] [PDF]
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S. Horie, H. Ishii, F. Matsumoto, M. Kusano, K. Kizaki, J. Matsuda, and M. Kazama Acceleration of Thrombomodulin Gene Transcription by Retinoic Acid. RETINOIC ACID RECEPTORS AND Sp1 REGULATE THE PROMOTER ACTIVITY THROUGH INTERACTIONS WITH TWO DIFFERENT SEQUENCES IN THE 5'-FLANKING REGION OF HUMAN GENE J. Biol. Chem., January 19, 2001; 276(4): 2440 - 2450. [Abstract] [Full Text] [PDF]
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Y. Yang, C. K. Hwang, E. Junn, G. Lee, and M. M. Mouradian ZIC2 and Sp3 Repress Sp1-induced Activation of the Human D1ADopamine Receptor Gene J. Biol. Chem., December 1, 2000; 275(49): 38863 - 38869. [Abstract] [Full Text] [PDF]
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T. Minami, R. D. Rosenberg, and W. C. Aird Transforming Growth Factor-beta 1-mediated Inhibition of the flk-1/KDR Gene Is Mediated by a 5'-Untranslated Region Palindromic GATA Site J. Biol. Chem., February 9, 2001; 276(7): 5395 - 5402. [Abstract] [Full Text] [PDF]
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S. J. Baek, J. M. Horowitz, and T. E. Eling Molecular Cloning and Characterization of Human Nonsteroidal Anti-inflammatory Drug-activated Gene Promoter. BASAL TRANSCRIPTION IS MEDIATED BY Sp1 AND Sp3 J. Biol. Chem., August 31, 2001; 276(36): 33384 - 33392. [Abstract] [Full Text] [PDF]
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