The Sequential Activation and Repression of the Human PDGF-B Gene During Chronic Hypoxia Reveals Antagonistic Roles for the Depletion of Oxygen and Glucose

Ullerås, Erik; Wilcock, Arwen C.; Miller, Stephen J.; Franklin, Gary

doi:10.3109/08977190109001089

Cited by 24 publications

(15 citation statements)

References 37 publications

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“…Although previous studies have shown that PDGF-B mRNA expression is regulated by hypoxia and HIF-1 in other cell types (24)(25)(26), it was not established whether PDGFB is a direct HIF-1 target gene, which requires the identification of a HIF-1-binding site within the context of a functional hypoxia response element. To address this question, we identified seven matches to the consensus HIF-binding site (HBS) sequence 5′-[A/G]CGTG-3′ in the human PDGFB gene (HBS1-7; green triangles in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Analysis of candidate hypoxia response elements in the PDGFB genomic sequence, including a candidate in the 5′-flanking sequence that previously was found to be nonfunctional (25), revealed that HIF-1, but not HIF-2, binds selectively to a site in intron 3 to activate PDGFB transcription, thereby delineating the molecular mechanism underlying previous observations of HIF-1-dependent induction of PDGF-B in hypoxic cells (24,32,33). Because coexpression of HIF-1α and PDGF-B in BCCs was required to establish the relevance of our findings, we confirmed that PDGF-B + cells in breast cancer orthografts were also HIF-1α + .…”

Section: Discussionmentioning

confidence: 99%

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Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Schito

Rey²,

Tafani

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

193

167

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Lymphatic dissemination from the primary tumor is a major mechanism by which breast cancer cells access the systemic circulation, resulting in distant metastasis and mortality. Numerous studies link activation of hypoxia-inducible factor 1 (HIF-1) with tumor angiogenesis, metastasis, and patient mortality. However, the role of HIF-1 in lymphatic dissemination is poorly understood. In this study, we show that HIF-1 promotes lymphatic metastasis of breast cancer by direct transactivation of the gene encoding platelet-derived growth factor B (PDGF-B), which has proliferative and chemotactic effects on lymphatic endothelial cells. Lymphangiogenesis and lymphatic metastasis in mice bearing human breast cancer orthografts were blocked by administration of the HIF-1 inhibitor digoxin or the tyrosine kinase inhibitor imatinib. Immunohistochemical analysis of human breast cancer biopsies demonstrated colocalization of HIF-1α and PDGF-B, which were correlated with lymphatic vessel area and histological grade. Taken together, these data provide experimental support for breast cancer clinical trials targeting HIF-1 and PDGF-B.lymph node | orthotopic transplantation | triple-negative breast cancer M etastasis is the major cause of mortality in breast cancer patients (1). Metastatic dissemination of cancer cells from the primary tumor may occur via blood vessels or lymphatic vessels (LVs). In breast cancer, the most clinically important predictor of distant organ metastasis and patient mortality is the presence and extent of axillary lymph node (LN) metastasis (1). Increased density of peritumoral and intratumoral LVs in breast cancer is significantly associated with LN metastasis and patient mortality (2). Two members of the vascular endothelial growth factor (VEGF) family, VEGF-C and VEGF-D, bind to VEGF receptor 3 on the surface of lymphatic endothelial cells (LECs) to stimulate growth of LVs (lymphangiogenesis) and cancer cell metastasis to LNs and distant sites (3, 4). VEGF-A, which primarily stimulates blood vessel angiogenesis, promotes lymphangiogenesis and LN metastasis, and members of the angiopoietin, FGF, insulin-like growth factor (IGF), and PDGF families also have been reported to promote lymphangiogenesis and metastasis (1, 5).Intratumoral hypoxia is a common finding in breast cancer, and severe hypoxia [pO 2 <10 mm Hg (∼1.5% O 2 )] is associated with a significantly increased risk of metastasis and patient mortality (6). A major mechanism by which hypoxia promotes metastasis is through the hypoxia-inducible factors (HIFs), which activate the transcription of genes that play key roles in many critical aspects of cancer biology, including angiogenesis, metabolic reprogramming, epithelial-mesenchymal transition, and tissue invasion (7). HIFs are heterodimers composed of an O 2 -regulated HIF-1α or HIF-2α subunit and a constitutively expressed HIF-1β subunit (7). HIF-1α is required for vascular metastasis from breast to lung in autochthonous (8) and orthotopic transplantation (9-11) mouse models.Clinical studies h...

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Schito

Rey²,

Tafani

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

193

167

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“…67 An HRE is also present in the PDGFB gene, although this may not necessarily be responsive to hypoxia. 85 PDGFB protein is secreted by podocytes during early glomerular development, which may be an important signal for recruitment of mesangioblasts, which express the PDGFB receptor, PDGFRβ. 86 Both PDGF and PDGFRβ become confined to the mesangium in later developmental stages, which may provide autocrine signals required for maturation of the mesangium.…”

Section: Assembly Of the Gbm Laminin And Type IV Collagen Networkmentioning

confidence: 99%

“…86 Both PDGF and PDGFRβ become confined to the mesangium in later developmental stages, which may provide autocrine signals required for maturation of the mesangium. 85 Axonal guidance receptors and ligands are also found in developing glomeruli, as they are in developing vessels elsewhere in the embryo. [87][88][89] For example, neuropilin-1 (Np1), a co-receptor with VEGFR2 for VEGF 164 (but lacking a cytoplasmic signaling motif ), immunolocalizes to glomerular endothelial cells.…”

Section: Assembly Of the Gbm Laminin And Type IV Collagen Networkmentioning

confidence: 99%

Development of kidney glomerular endothelial cells and their role in basement membrane assembly

Abrahamson

2009

Organogenesis

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Data showing that the embryonic day 12 (E12) mouse kidney contains its own pool of endothelial progenitor cells is presented.Mechanisms that regulate metanephric endothelial recruitment and differentiation, including the hypoxia-inducible transcription factors and vascular endothelial growth factor/vascular endothelial growth factor receptor signaling system, are also discussed. Finally, evidence that glomerular endothelial cells contribute importantly to assembly of the glomerular basement membrane (GBM), especially the laminin component, is reviewed. Together, this forum offers insights on blood vessel development in general, and formation of the glomerular capillary in particular, which inarguably is among the most unique vascular structures in the body. IntroductionDr. Dale Abrahamson, University Distinguished Professor and Chair, Department of Anatomy and Cell Biology, University of Kansas Medical Center: In almost every example of primary glomerular disease (including postinfection glomerulonephritis, immunoglobulin A nephropathy, anti-GBM disease, minimal change nephrotic syndrome, focal segmental glomerulosclerosis, mesangioproliferative disease, hereditary nephritis) and metabolic or hematological diseases affecting the kidney (including diabetes mellitus, lupus, HIV), the normal architecture of the glomerular capillary wall is disrupted. These changes include loss of fenestrae and detachment of endothelial cells, focal or diffuse thickening of the GBM, and effacement and detachment of podocyte foot processes. Despite the critical importance of the glomerulus in filtration, many fundamental questions exist regarding normal glomerular development and maintenance.The GBM has long been considered to be a critical element in establishing the filtration barrier properties of the glomerular capillary. Supporting evidence has come from several decades of work using a variety of experimental physiological, pathobiological and ultrastructural tracer techniques showing that an intact GBM is essential for maintenance of normal glomerular permselective sieving properties. During the past several years, these findings have been confirmed (A) in knockout mice with targeted deficiencies in certain GBM laminin and type IV collagen chains; (B) in integrin deficient mice which lack appropriate basement membrane protein receptors in their plasma membranes; and (C) through the molecular genetic and biochemical definition of human Alport disease. More recently, as constituents of the epithelial slit diaphragm complex have been progressively revealed, a great deal of excitement and emphasis has understandably been placed on the podocyte and its role in the glomerular filtration barrier. Nevertheless, a growing realization has also developed among many investigators that no single layer of the glomerular capillary can, by itself, represent the primary barrier. Indeed, a basic tenet of cell biology is that cells and their associated extracellular matrices form an intimate microenvironment crucial for tissue differentiation and...

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“…Similarly, the PDGFB gene promoter contains an HRE, although by itself it may not be functionally responsive to hypoxia (67). Mesangial cells are derived from metanephric precursors that do not express Flk1 and therefore are distinct from the endothelial developmental pathway (68).…”

Section: Role For Hif In Metanephric Kidney Developmentmentioning

confidence: 99%

Hypoxia-Inducible Factors and Kidney Vascular Development

Freeburg¹,

Abrahamson²

2003

Journal of the American Society of Nephrology

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Abstract. Among the genes strongly induced by hypoxia-inducible factors (HIF) and highly expressed during kidney microvascular development is vascular endothelial growth factor, which encodes a potent endothelial mitogen and chemoattractant critical for embryonic vasculogenesis and angiogenesis. In developing kidney, glomerular podocytes are particularly rich sources of vascular endothelial growth factor, which probably serves to attract endothelial precursors into vascular clefts of immature glomeruli, promote their mitosis and differentiation into glomerular endothelial cells, and assist with maintenance of their highly differentiated state through maturation. This article summarizes the structure, function, and expression of HIF and discusses HIF target genes expressed during kidney vascular development. Furthermore, it is speculated that different HIF heterodimers are stabilized in different cell populations, which may lead to cell-selective induction of HIF target genes important for renal vasculogenesis/angiogenesis.

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The Sequential Activation and Repression of the Human PDGF-B Gene During Chronic Hypoxia Reveals Antagonistic Roles for the Depletion of Oxygen and Glucose

Cited by 24 publications

References 37 publications

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells

Development of kidney glomerular endothelial cells and their role in basement membrane assembly

Hypoxia-Inducible Factors and Kidney Vascular Development

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