New Insights into the Functions of Histidine-Rich Glycoprotein

Wakabayashi, Shigeo

doi:10.1016/b978-0-12-407696-9.00009-9

Cited by 36 publications

(49 citation statements)

References 101 publications

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“…The different HRG domains may mediate different aspects of the multifaceted biology ascribed to HRG [4], [5], [7]. HRG bioactivity has been suggested by ourselves [17], and others [18], to involve HRG degradation.…”

Section: Discussionmentioning

confidence: 99%

“…HRG's biological activity is dependent on binding of Zn 2+ to the His-Pro domain [5]. The histidine residues in the His-Pro domain as well as the N-terminus of HRG bind heparan sulfate (HS) [6], [7]. The three-dimensional structure of HRG has not been solved, but the presence of several intramolecular disulfide bridges [8] indicates that native HRG attains a tight, globular conformation.…”

Section: Introductionmentioning

confidence: 99%

“…Gene knockout of hrg does not interfere with embryonic development, but is accompanied by increased clot formation as well as increased fibrinolysis [13]. There are a few cases of familial HRG mutations that result in reduced plasma HRG levels without a direct correlation with thrombotic events [7]. A potential hemostatic role of HRG could mechanistically be due to its interaction with both fibrinogen and thrombospondin [13].…”

Section: Introductionmentioning

confidence: 99%

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Histidine-Rich Glycoprotein Uptake and Turnover Is Mediated by Mononuclear Phagocytes

et al. 2014

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Histidine-rich glycoprotein (HRG) is implicated in tumor growth and metastasis by regulation of angiogenesis and inflammation. HRG is produced by hepatocytes and carried to tissues via the circulation. We hypothesized that HRG's tissue distribution and turnover may be mediated by inflammatory cells. Biodistribution parameters were analyzed by injection of radiolabeled, bioactive HRG in the circulation of healthy and tumor-bearing mice. 125I-HRG was cleared rapidly from the blood and taken up in tissues of healthy and tumor-bearing mice, followed by degradation, to an increased extent in the tumor-bearing mice. Steady state levels of HRG in the circulation were unaffected by the tumor disease both in murine tumor models and in colorectal cancer (CRC) patients. Importantly, stromal pools of HRG, detected in human CRC microarrays, were associated with inflammatory cells. In agreement, microautoradiography identified 125I-HRG in blood vessels and on CD45-positive leukocytes in mouse tissues. Moreover, radiolabeled HRG bound in a specific, heparan sulfate-independent manner, to differentiated human monocytic U937 cells in vitro. Suppression of monocyte differentiation by systemic treatment of mice with anti-colony stimulating factor-1 neutralizing antibodies led to reduced blood clearance of radiolabeled HRG and to accumulation of endogenous HRG in the blood. Combined, our data show that mononuclear phagocytes have specific binding sites for HRG and that these cells are essential for uptake of HRG from blood and distribution of HRG in tissues. Thereby, we confirm and extend our previous report that inflammatory cells mediate the effect of HRG on tumor growth and metastatic spread.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Histidine-Rich Glycoprotein Uptake and Turnover Is Mediated by Mononuclear Phagocytes

et al. 2014

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“…It is produced in the liver, but it has also been reported to be synthesized by monocytes, macrophages and megakaryocytes [1]. However, no HPRG mRNA was found in immune tissues by RT-PCR analysis, indicating that the HPRG present in immune cells is acquired from plasma [2].…”

Section: Introductionmentioning

confidence: 97%

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Ronca

Raggi

2015

Biochimie

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“…Histidine Rich Glycoprotein codes for a protein found in plasma thought to promote thrombosis, inhibit angiogenesis, and regulate immunity (26)(27)(28)(29)(30). Although no studies have yet reported a link between Histidine Rich Glycoprotein and IPAH, it is possible that altered protein function could predispose to in situ thrombosis, a pathologic feature of IPAH.…”

Section: Relevance Of Top Three Wes Hits To Ipah Pathobiologymentioning

confidence: 99%

Whole-Exome Sequencing Reveals TopBP1 as a Novel Gene in Idiopathic Pulmonary Arterial Hypertension

Perez

Yuan

Lyuksyutova

et al. 2014

Am J Respir Crit Care Med

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Rationale: Idiopathic pulmonary arterial hypertension (IPAH) is a life-threatening disorder characterized by progressive loss of pulmonary microvessels. Although mutations in the bone morphogenetic receptor 2 (BMPR2) are found in 80% of heritable and z15% of patients with IPAH, their low penetrance (z20%) suggests that other unidentified genetic modifiers are required for manifestation of the disease phenotype. Use of whole-exome sequencing (WES) has recently led to the discovery of novel susceptibility genes in heritable PAH, but whether WES can also accelerate gene discovery in IPAH remains unknown.Objectives: To determine whether WES can help identify novel gene modifiers in patients with IPAH.Methods: Exome capture and sequencing was performed on genomic DNA isolated from 12 unrelated patients with IPAH lacking BMPR2 mutations. Observed genetic variants were prioritized according to their pathogenic potential using ANNOVAR. Measurements and Main Results:A total of nine genes were identified as high-priority candidates. Our top hit was topoisomerase DNA binding II binding protein 1 (TopBP1), a gene involved in the response to DNA damage and replication stress. We found that TopBP1 expression was reduced in vascular lesions and pulmonary endothelial cells isolated from patients with IPAH. Although TopBP1 deficiency made endothelial cells susceptible to DNA damage and apoptosis in response to hydroxyurea, its restoration resulted in less DNA damage and improved cell survival.Conclusions: WES led to the discovery of TopBP1, a gene whose deficiency may increase susceptibility to small vessel loss in IPAH. We predict that use of WES will help identify gene modifiers that influence an individual's risk of developing IPAH.

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New Insights into the Functions of Histidine-Rich Glycoprotein

Cited by 36 publications

References 101 publications

Histidine-Rich Glycoprotein Uptake and Turnover Is Mediated by Mononuclear Phagocytes

Histidine-Rich Glycoprotein Uptake and Turnover Is Mediated by Mononuclear Phagocytes

Structure-function relationships in mammalian histidine-proline-rich glycoprotein

Whole-Exome Sequencing Reveals TopBP1 as a Novel Gene in Idiopathic Pulmonary Arterial Hypertension

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