Inducible platelet-derived growth factor D-chain expression by angiotensin II and hydrogen peroxide involves transcriptional regulation by Ets-1 and Sp1.

Platelet-derived growth factor D-chain (PDGF-D) is the newest member of the PDGF family of mitogens and chemoattractants expressed in a wide variety of cell types, including vascular smooth muscle cells (SMCs). The molecular mechanisms regulating PDGF-D transcription are not known. Primer extension analysis mapped a single transcriptional start site to the ccAGCGC motif with several potential Ets motifs located upstream. Ets-1, but not Ets-1 bearing only the DNA-binding domain, activates the PDGF-D promoter and mRNA expression in SMCs. Ets site D3 ((-470)GGAT(-467)) is singly required for basal and Ets-1-inducible PDGF-D promoter-dependent expression. D3 supports the interaction of endogenous and recombinant Ets-1 and Sp1. Sp1, like Ets-1, induces PDGF-D transcription and mRNA expression, which is blocked by mutant Ets-1. H2O2 stimulates Ets-1, but not Sp1, and activates D3-dependent PDGF-D transcription. Ets-1 and Sp1 siRNA block peroxide-inducible PDGF-D expression. Angiotensin II (ATII) induction of PDGF-D and Ets-1 was blocked by prior incubation of the cells with PEG-catalase, but not BSA, indicating that ATII-inducible Ets-1 and PDGF-D expression is mediated via H2O2. Thus, 2 separate trans-acting factors regulate PDGF-D transcription, alone and in response to oxidative stress.

[1]  Robert Tjian,et al.  Isolation of cDNA encoding transcription factor Sp1 and functional analysis of the DNA binding domain , 1987, Cell.

[2]  R. Ross,et al.  PLATELET-DERIVED GROWTH FACTOR , 1989, The Lancet.

[3]  T. Oka,et al.  Structural and functional analysis of the regulatory sequences of the ets-1 gene. , 1991, Oncogene.

[4]  B. Wasylyk,et al.  The Ets family of transcription factors. , 1993, European journal of biochemistry.

[5]  R. Ross.  Atherosclerosis: current understanding of mechanisms and future strategies in therapy. , 1993, Transplantation proceedings.

[6]  J. H. Chen,et al.  PEA3, Oct 1 and Oct 2 positively regulate the human ETS1 promoter. , 1993, Oncogene.

[7]  Amyj . Williams,et al.  Interplay of Sp1 and Egr-1 in the Proximal Platelet-derived Growth Factor A-Chain Promoter in Cultured Vascular Endothelial Cells (*) , 1995, The Journal of Biological Chemistry.

[8]  T. Werner,et al.  MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. , 1995, Nucleic acids research.

[9]  Amyj . Williams,et al.  Egr-1-Induced Endothelial Gene Expression: A Common Theme in Vascular Injury , 1996, Science.

[10]  C. Betsholtz,et al.  Platelet-derived growth factor: a key regulator of connective tissue cells in embryogenesis and pathogenesis. , 1997, Kidney international.

[11]  S. Smale,et al.  Transcription initiation from TATA-less promoters within eukaryotic protein-coding genes. , 1997, Biochimica et biophysica acta.

[12]  R. Alexander,et al.  Angiotensin II induces monocyte chemoattractant protein-1 gene expression in rat vascular smooth muscle cells. , 1998, Circulation research.

[13]  R. Alexander,et al.  Reactive Oxygen Species Mediate the Activation of Akt/Protein Kinase B by Angiotensin II in Vascular Smooth Muscle Cells* , 1999, The Journal of Biological Chemistry.

[14]  C. Heldin,et al.  Mechanism of action and in vivo role of platelet-derived growth factor. , 1999, Physiological reviews.

[15]  S. Naito,et al.  Stimulation of in vitro angiogenesis by hydrogen peroxide and the relation with ETS-1 in endothelial cells. , 1998, Life sciences.

[16]  J. Rothberg,et al.  PDGF-D, a new protease-activated growth factor , 2001, Nature Cell Biology.

[17]  C. Heldin,et al.  Involvement of platelet-derived growth factor in disease: development of specific antagonists. , 2001, Advances in cancer research.

[18]  K. Alitalo,et al.  Chromosomal Location, Exon Structure, and Vascular Expression Patterns of the Human PDGFC and PDGFD Genes , 2001, Circulation.

[19]  C. Heldin,et al.  PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor. , 2001, Nature cell biology.

[20]  M. Jeffers,et al.  Platelet-derived growth factor D: tumorigenicity in mice and dysregulated expression in human cancer. , 2002, Cancer research.

[21]  C. Alpers,et al.  Platelet-derived growth factor-D expression in developing and mature human kidneys. , 2002, Kidney international.

[22]  L. Khachigian,et al.  NF1/X represses PDGF A‐chain transcription by interacting with Sp1 and antagonizing Sp1 occupancy of the promoter , 2002, The EMBO journal.

[23]  Xuri Li,et al.  PDGF-D is a potent transforming and angiogenic growth factor , 2003, Oncogene.

[24]  Xuri Li,et al.  Novel PDGF family members: PDGF-C and PDGF-D. , 2003, Cytokine & growth factor reviews.

[25]  H. Kim,et al.  A Potential Oncogenic Activity of Platelet-Derived Growth Factor D in Prostate Cancer Progression , 2004, Cancer Research.

[26]  K. Alitalo,et al.  PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. , 2004, Blood.

[27]  Levon M Khachigian,et al.  Ets-1 Stimulates Platelet-Derived Growth Factor A-Chain Gene Transcription and Vascular Smooth Muscle Cell Growth via Cooperative Interactions With Sp1 , 2004, Circulation research.

[28]  T. Sjöblom,et al.  Platelet-derived growth factor production by B16 melanoma cells leads to increased pericyte abundance in tumors and an associated increase in tumor growth rate. , 2004, Cancer research.

[29]  D. Pimentel,et al.  S-Glutathiolation of Ras Mediates Redox-sensitive Signaling by Angiotensin II in Vascular Smooth Muscle Cells*[boxs] , 2004, Journal of Biological Chemistry.