Identification and characterization of PF4varl, a human gene variant of platelet factor 4.

Green, C J; Charles, R. St; Edwards, Brian F.P.; Johnson, Paul

doi:10.1128/mcb.9.4.1445

Cited by 55 publications

(34 citation statements)

References 38 publications

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“…8 The critical role of CXCL4 in several pathophysiologic conditions is further underlined by the existence in human beings of a highly homologous gene encoding a variant of CXCL4, named as CXCL4L1. [18][19][20] CXCL4L1, compared with For personal use only. on May 12, 2018. by guest www.bloodjournal.org From CXCL4, exhibits significantly reduced heparin-binding properties and thus a lower sequestration by glycosaminoglycans.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies hypothesized that this may imply a difference in the cell type in which CXCL4L1 is expressed or a difference in its mode of secretion. 19 However, this hypothesis has not yet been verified. The online version of this article contains a data supplement.…”

mentioning

confidence: 97%

“…Indeed, more than a decade ago a second, highly homologous gene, showing only 2.6% DNA divergence was identified and called PF-4alt 18 or PF4-V1. 19 More recently, the protein product of the PF-4alt gene was isolated for the first time from thrombinstimulated human platelets and renamed as CXCL4L1. 20 CXCL4L1, compared with CXCL4, is a 30-fold more potent inhibitor of EC chemotaxis in vitro and has more profound effects in blocking angiogenesis in vivo.…”

Section: Introductionmentioning

confidence: 99%

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PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion

Lasagni

Grépin

Mazzinghi

et al. 2007

Blood

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PF-4/CXCL4 is a member of the CXC chemokine family, which is mainly produced by platelets and known for its pleiotropic biological functions. Recently, the proteic product of a nonallelic variant gene of CXCL4 was isolated from human platelets and named as CXCL4L1. CXCL4L1 shows only 4.3% amino acid divergence in the mature protein, but exhibits a 38% amino acid divergence in the signal peptide region. We hypothesized that this may imply a difference in the cell type in which CXCL4L1 is expressed or a difference in its mode of secretion. In different types of transfected cells, CXCL4 and CXCL4L1 exhibited a distinct subcellular localization and a differential regulation of secretion, CXCL4 being stored in secretory granules and released in response to protein kinase C activation, whereas CXCL4L1 was continuously synthesized and secreted through a constitutive pathway. A protein kinase C-regulated CXCL4 secretion was observed also in lymphocytes, a cell type expressing mainly CXCL4 mRNA, whereas smooth muscle cells, which preferentially expressed CXCL4L1, exhibited a constitutive pathway of secretion. These results demonstrate that CXCL4 and CXCL4L1 exhibit a distinct subcellular localization and are secreted in a differentially regulated manner, suggesting distinct roles in inflammatory or homeostatic processes. IntroductionPF-4/CXCL4 is a member of the CXC chemokine family produced by cells of the megakaryocytic lineage. In megakaryocytes CXCL4 is synthesized, enclosed in vesicles, and transferred to the ␣ granules from which it is secreted following platelet activation. 1 More recently, CXCL4 expression was also found in monocytes. 2 The first biological function described for CXCL4 is its antiheparin activity, responsible for the important role of CXCL4 in the regulation of coagulation processes. 3 In addition, CXCL4 has a role in heparin-induced thrombocytopenia (HIT), a common immune-mediated disorder characterized by an immune response against epitopes within circulating heparin-CXCL4 complexes, which leads to a reduction of circulating platelets counts and is recognized as a risk factor for thromboembolic complications. 4,5 Subsequent studies have defined an array of apparently unrelated CXCL4 activities. CXCL4 exhibits antiangiogenic properties in vitro and in vivo and inhibits tumor neovascularization through a variety of mechanisms. [6][7][8] First, CXCL4 is able to interact directly with angiogenic growth factors, such as fibroblast growth factors (FGFs) and vascular endothelial growth factor (VEGF), and inhibits their interaction with the cell surface receptor. 6,9 Second, CXCL4 may bind proteoglycans and interfere with the proteoglycan-bystander effect on growth factor activity. 10 Furthermore, a cell surface receptor that is expressed by human endothelial cells (ECs) in a cell cycle-dependent manner 11 and mediates the antiangiogenic effects of CXCL4 has been recently identified and named as Besides the antiangiogenic properties, CXCL4 expresses immunomodulatory activities, such as down-regulatio...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

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PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion

Lasagni

Grépin

Mazzinghi

et al. 2007

Blood

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“…Other studies have reported that the inhibitory effect of CXCL4 is mediated through complex formation with bFGF or CXCL8 (53,55). Finally, CXCL4 also exists as a non-allelic gene variant, CXCL4L1, which differs from CXCL4 in its signalling region, subcellular localization, and regulation of secretion (56)(57)(58). CXCL4L1 has been found to be a more potent inhibitor of angiogenesis both in in-vitro and in in-vivo models of angiogenesis (59), but the mechanism by which this variant mediates these effects is yet to be defined.…”

Section: Chemokine-mediated Inhibition Of Angiogenesis Via Undefined mentioning

confidence: 99%

Chemokines as mediators of angiogenesis

Mehrad¹,

Keane²,

Strieter³

2007

Thromb Haemost

180

145

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SummaryChemokines were originally described as cytokines that mediate leukocyte recruitment to sites of inflammation. Members of a subgroup of chemokines, the CXC family, also play a critical role in both physiologic and pathologic angiogenesis, including in the context of chronic inflammation, fibrosis, and malignancy. A unique feature of this family of cytokines is that, on the basis of their structure and receptor binding, individual ligands display either angiogenic or angiostatic biological activity in the regulation of angiogenesis. In this review, we summarize the key literature in this growing field.

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“…The proposed receptor for CXCL4/PF-4, named CXCR3-B (14), might not mediate all its effects. The variant of CXCL4/PF-4, encoded by a second nonallelic gene and differing in only three amino acids, is named CXCL4L1/PF-4var (15,16) and was isolated from thrombin-stimulated platelets (17). In a previous study, we showed that CXCL4L1/PF4var is also produced by osteosarcoma cells (18).…”

Section: Introductionmentioning

confidence: 99%

The COOH-Terminal Peptide of Platelet Factor-4 Variant (CXCL4L1/PF-4var47-70) Strongly Inhibits Angiogenesis and Suppresses B16 Melanoma Growth In vivo

Vandercappellen

Liekens

Bronckaers

et al. 2010

Molecular Cancer Research

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Chemokines influence tumor growth directly or indirectly via both angiogenesis and tumor-leukocyte interactions. Platelet factor-4 (CXCL4/PF-4), which is released from α-granules of activated platelets, is the first described angiostatic chemokine. Recently, it was found that the variant of CXCL4/PF-4 (CXCL4L1/PF4var) could exert a more pronounced angiostatic and antitumoral effect than CXCL4/PF-4. However, the molecular mechanisms of the angiostatic activities of the PF-4 forms remain partially elusive. Here, we studied the biological properties of the chemically synthesized COOH-terminal peptides of CXCL4/PF-4 (CXCL4/PF-4 47-70 ) and CXCL4L1/PF-4var (CXCL4L1/PF-4var ). Both PF-4 peptides lacked monocyte and lymphocyte chemotactic activity but equally well inhibited (25 nmol/L) endothelial cell motility and proliferation in the presence of a single stimulus (i.e., exogenous recombinant fibroblast growth factor-2). In contrast, when assayed in more complex angiogenesis test systems characterized by the presence of multiple mediators, including in vitro wound-healing (2.5 nmol/L versus 12.5 nmol/L), Matrigel (60 nmol/L versus 300 nmol/L), and chorioallantoic membrane assays, CXCL4L1/PF-4var 47-70 was found to be significantly (5-fold) more angiostatic than CXCL4/PF-4 47-70 . In addition, low (7 μg total) doses of intratumoral CXCL4L1/ PF-4var 47-70 inhibited B16 melanoma growth in mice more extensively than CXCL4/PF-4 47-70 . This antitumoral activity was predominantly mediated through inhibition of angiogenesis (without affecting blood vessel stability) and induction of apoptosis, as evidenced by immunohistochemical and fluorescent staining of B16 tumor tissue. In conclusion, CXCL4L1/PF-4var 47-70 is a potent antitumoral and antiangiogenic peptide. These results may represent the basis for the design of CXCL4L1/PF-4var COOH-terminal-derived peptidomimetic anticancer drugs. Mol Cancer Res; 8(3); 322-34. ©2010 AACR.

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Identification and characterization of PF4varl, a human gene variant of platelet factor 4.

Cited by 55 publications

References 38 publications

PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion

PF-4/CXCL4 and CXCL4L1 exhibit distinct subcellular localization and a differentially regulated mechanism of secretion

Chemokines as mediators of angiogenesis

The COOH-Terminal Peptide of Platelet Factor-4 Variant (CXCL4L1/PF-4var47-70) Strongly Inhibits Angiogenesis and Suppresses B16 Melanoma Growth In vivo

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