Tumor suppressor p53 regulates heparanase gene expression

Baraz, Lea; Haupt, Ygal; Elkin, Michael; Peretz, Tamar; Vlodavsky, Israël

doi:10.1038/sj.onc.1209425

Cited by 103 publications

(99 citation statements)

References 52 publications

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“…Of note, in mouse embryonic fibroblasts and cancer cells, others found that p53 binds to the heparanase promoter and inhibits its activity. 75 Moreover, we found aging and p53 overexpression to be associated with increased expression of PTEN, a negative regulator of protein kinase B (Akt), also induced by Egr1. Previous studies have established a role of the PI3K/Akt pathway in the suppression of TF in endothelial cells, 76,77 and p53-dependent modulation of PTEN could underlie the observed changes in endothelial TF expression and possibly also the absence of venous thrombosis in aged Endp53-KO mice.…”

Section: Discussionmentioning

confidence: 95%

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Bochenek

Bauer

Gogiraju³

et al. 2018

Blood Advances

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Key Points• Deletion of p53 in endothelial cells prevents venous thrombosis in aged, but not in adult, mice.• Neutralization of heparanase in aged mice using TFPI2 peptides restores the thrombotic phenotype of adult mice. End.p53-KO mice were protected from vein thrombosis. Analysis of primary endothelial cells from aged mice or human vein endothelial cells after induction of replicative senescence revealed significantly increased early growth response gene-1 (Egr1) and heparanase expression, and plasma factor Xa levels were elevated in aged End.p53-WT, but not in End.p53-KO mice. Increased endothelial Egr1 and heparanase expression also was observed after doxorubicin-induced p53 overexpression, whereas p53 inhibition using pifithrin-a reduced tissue factor (TF) expression. Importantly, inhibition of heparanase activity using TF pathway inhibitor-2 (TFPI2) peptides prevented the enhanced venous thrombus formation in aged mice and restored it to the thrombotic phenotype of adult mice.Our findings suggest that p53 accumulation and heparanase overexpression in senescent endothelial cells are critically involved in mediating the increased risk of venous thrombosis with age and that heparanase antagonization may be explored as strategy to ameliorate the prothrombotic endothelial phenotype with age.

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Section: Discussionmentioning

confidence: 95%

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

Bochenek

Bauer

Gogiraju³

et al. 2018

Blood Advances

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“…46 -49 p53 modulates expression of protein regulators of extracellular heparin sulfate, such as heparanase and extracellular heparin sulfate 6-O-endosulfatases. 50 Transgenic mice overexpressing WT p53 in the kidney exhibit differentiation defects in the UB. 51 A consequence of abnormal signaling to the MM by the UB is increased mesenchymal apoptosis and decreased mesenchyme to epithelial transition, resulting in hypoplastic kidneys.…”

Section: Discussionmentioning

confidence: 99%

p53 Regulates Metanephric Development

Saifudeen

Dipp

Stefkova

et al. 2009

Journal of the American Society of Nephrology

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p53 is best known as a tumor suppressor that regulates cell-cycle, differentiation, and apoptosis pathways, but its potential role in embryonic development and organogenesis remains controversial. Here, p53Ϫ/Ϫ embryos bred on C57Bl6 background exhibited a spectrum of congenital abnormalities of the kidney and urinary tract, including ureteric bud (UB) ectopia, double ureters/collecting systems, delayed primary branching of the UB, and hypoplastic metanephroi. We observed ectopic UB outgrowth from the Wolffian duct (WD) in one third of p53 Ϫ/Ϫ embryos. The prevalence of duplex was higher in embryos than in neonates, and ex vivo organ culture suggested that ectopic ureters can regress over time, leaving behind a dysplastic pole ("segmental dysgenesis"). Transgenic expression of dominant negative p53 or conditional inactivation of p53 in the UB but not in the metanephric mesenchyme lineage recapitulated the duplex phenotype. Mechanistically, p53 inactivation in the WD associated with enhanced sensitivity to glial cell line-derived neurotrophic factor (GDNF)-induced ectopic budding and potentiated phosphatidylinositol-3 kinase activation by GDNF in UB cells. Unlike several other models of UB ectopia, hypersensitivity of p53 Ϫ/Ϫ WD to GDNF is not accompanied by reduced Sprouty-1 or anterior expansion of the GDNF domain. In summary, our data lend support for a restrictive role for p53 activity in UB outgrowth from the WD. Organogenesis is dependent on a multitude of growth factors, signaling molecules, and transcription factors that temporally and spatially define a developmental program. Metanephric development is dependent on formation of the Wolffian duct (WD) and the adjacent metanephric mesenchyme (MM) from the intermediate mesoderm. In mice, the ureteric bud (UB) develops at embryonic day 10.5 (E10.5) from the caudal end of the WD. Inductive interactions between the UB and the MM ensure cell survival and subsequent onset of metanephrogenesis. Emergence of the UB from a specific site in the WD adjacent to the MM is controlled by the glial cell line-derived neurotrophic factor (GDNF)-cRet signaling pathway. 1-6 GDNF is a growth factor that is secreted by the MM and binds to its receptor c-Ret and co-receptor GFR␣1 that are expressed along the WD and UB tips. Stimulation of the GDNF-cRet pathway results in cell proliferation and chemotaxis. 7,8 After the initial broad distribution of the GDNF field along the posterior half of the WD, the GDNF expression domain is progressively restricted to the caudal end of the WD in the immediate vicinity of the site of UB outgrowth 9 -11 ; however, the potential for bud emergence remains along the length of the WD, which continues to express the c-Ret/GFR␣1 receptor/co-receptor. Evidence from mutant mouse models and metanephric organ culture implicates impaired restriction of the GDNF field and the GDNF/c-Ret signaling pathway in ureter duplica-

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“…Elastase (Levidiotis et al 2001), tissue plasminogen activator (Vlodavsky et al 1990), thrombin (Benezra et al 1992), high levels of glucose in serum (Levidiotis et al 2001;Maxhimer et al 2005), reninangiotensin-aldosteron activity with angiotensin II (Kramer et al 2006) and aldosteron (Kramer et al 2006), freeradicals (Kramer et al 2006), proinflammatory cytokines, fatty acids, tumor necrosis factor (TNF)-a, interleukin-1b (Chen et al 2004), and mutant p53 variant (Baraz et al 2006) support the expression and/or activity of heparanase. Heparanase promoter and a 25 mmol/l glucose solution together induce luciferase reporter gene activity (the luciferase gene is connected with the heparanase promoter) (Maxhimer et al 2005).…”

Section: Heparanase: Regulationmentioning

confidence: 99%

The Role of Heparanase in Diseases of the Glomeruli

Szymczak

Kuźniar

Klinger

2010

Arch. Immunol. Ther. Exp.

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The glomerular basement membrane (GBM) is a kind of net that remains in a state of dynamic equilibrium. Heparan sulfate proteoglycans (HSPGs) are among its most important components. There are much data indicating the significance of these proteoglycans in protecting proteins such as albumins from penetrating to the urine, although some new data indicate that loss of proteoglycans does not always lead to proteinuria. Heparanase is an enzyme which cleaves beta 1,4 D: -glucuronic bonds in sugar groups of HSPGs. Thus it is supposed that heparanase may have an important role in the pathogenesis of proteinuria. Increased heparanase expression and activity in the course of many glomerular diseases was observed. The most widely documented is the significance of heparanase in the pathogenesis of diabetic nephropathy. Moreover, heparanase acts as a signaling molecule and may influence the concentrations of active growth factors in the GBM. It is being investigated whether heparanase inhibition may cause decreased proteinuria. The heparanase inhibitor PI-88 (phosphomannopentaose sulfate) was effective as an antiproteinuric drug in an experimental model of membranous nephropathy. Nevertheless, this drug is burdened by some toxicity, so further investigations should be considered.

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Tumor suppressor p53 regulates heparanase gene expression

Cited by 103 publications

References 52 publications

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

The endothelial tumor suppressor p53 is essential for venous thrombus formation in aged mice

p53 Regulates Metanephric Development

The Role of Heparanase in Diseases of the Glomeruli

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