Inhibition of endothelial cell proliferation by platelet factor-4 involves a unique action on S phase progression.

Gupta, Shalley K.; Singh, Jai Pal

doi:10.1083/jcb.127.4.1121

Cited by 110 publications

(83 citation statements)

References 30 publications

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“…PF-4 is a tetrameric, lysine-rich member of the CXC chemokine family and is produced almost exclusively by megakaryocytes. PF-4 is an important modulator of endothelial cell proliferation Gupta and Singh, 1994) and angiogenesis (Sharpe et al, 1990;Hagedorn et al, 2001). PF-4 may influence tumor growth by modifying the effects of vascular endothelial growth factor or by binding and neutralizing heparin and other sulfated glycosaminoglycans that are required for the binding of proangiogenic factors (Gengrinovitch et al, 1995;Perollet et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Serum protein signature may improve detection of ductal carcinoma in situ of the breast

et al. 2009

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Ductal carcinoma in situ (DCIS) of the breast is part of a spectrum of preinvasive lesions that originate within normal breast tissue and progress to invasive breast cancer. The detection of DCIS is important for the reduction of mortality from breast cancer, but the diagnosis of preinvasive breast tumors is hampered by the lack of an adequate detection method. To identify the changes in protein expression during the initial stage of tumorigenesis and to identify the presence of new DCIS markers, we analysed serum from 60 patients with breast cancer and 60 normal controls using mass spectrometry. A 23-protein index was generated that correctly distinguishes the DCIS and control groups with sensitivities and specificities in excess of 80% in two independent cohorts. Two candidate peptides were purified and identified as platelet factor 4 (PF-4) and complement C3a desArg anaphylatoxin (C3a desArg ) using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In an independent serum set of 165 patients, PF-4 and C3a desArg were significantly upregulated in DCIS compared with non-cancerous controls, as validated using western blot and enzyme-linked immunosorbent assay. We conclude that our serum protein-based test, used in conjunction with image-based screening practices, could improve the sensitivity and specificity of breast cancer detection.

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Section: Discussionmentioning

confidence: 99%

Serum protein signature may improve detection of ductal carcinoma in situ of the breast

et al. 2009

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“…Although first recognized to bind heparin and act as an anticoagulant, PF4 is also known as an anti-angiogenic agent (11). On the other hand, IL8 binds heparin more weakly and can promote angiogenesis (11,12). The angiogenic functional difference may be due, at least in part, to N-terminal sequence differences.…”

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confidence: 99%

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confidence: 99%

Platelet Factor 4 and Interleukin-8 CXC Chemokine Heterodimer Formation Modulates Function at the Quaternary Structural Level

Nesmelova

Sham

Dudek

et al. 2005

Journal of Biological Chemistry

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The apparent complexity of biology increases as more biomolecular interactions that mediate function become known. We have used NMR spectroscopy and molecular modeling to provide direct evidence that tetrameric platelet factor-4 (PF4) and dimeric interleukin-8 (IL8), two members of the CXC chemokine family, readily interact by exchanging subunits and forming heterodimers via extension of their antiparallel ␤-sheet domains. We further demonstrate using functional assays that PF4/IL8 heterodimerization has a direct and significant consequence on the biological activity of both chemokines. Formation of heterodimers enhances the anti-proliferative effect of PF4 on endothelial cells in culture, as well as the IL8-induced migration of CXCR2 vector-transfected Baf3 cells. These results suggest that CXC chemokine biology, and perhaps cytokine biology in general, may be functionally modulated at the molecular level by formation of heterodimers. This concept, in turn, has implications for designing chemokine/cytokine variants with modified biological properties.Platelet factor-4 (PF4) 1 and interleukin-8 (IL8) are members of the CXC chemokine family of small (8 -10 kDa) proteins, a subfamily of chemokines within the cytokine superfamily (1). CXC chemokines are generally chemotactic for migratory immune cells, and thus are involved in the regulation of inflammatory processes and wound healing (1-4). In addition, they demonstrate biological activities in hematopoiesis, cell proliferation, angiogenesis, and glycosaminoglycan binding (1-4).CXC chemokines, which are known to self-associate as dimers and tetramers, exhibit high sequence and three-dimensional structural homology at both the tertiary (monomer) and quaternary (dimer and tetramer) levels. Each folded CXC chemokine monomer has an aperiodic, two-disulfide bond-stabilized N-terminal segment, followed by a three-stranded antiparallel ␤-sheet domain, and a C-terminal ␣-helix that is folded onto the generally amphipathic ␤-sheet (5). Dimers are formed by intermolecularly extending the monomer ␤-sheet into a sixstranded antiparallel ␤-sheet (originally termed AB-type dimer (6)). Tetramers are formed by ␤-sheet sandwiching of two ABtype dimers (6). Native PF4 dimers associate asymmetrically into tetramers (6), whereas in an N-terminal PF4 chimera (PF4M2), dimers associate symmetrically into tetramers with little change in biological activity (7). IL8 forms AB-type dimers and is not known to tetramerize (8 -10).Despite sequence and structure similarities, PF4 and IL8 mediate different biological activities. Although first recognized to bind heparin and act as an anticoagulant, PF4 is also known as an anti-angiogenic agent (11). On the other hand, IL8 binds heparin more weakly and can promote angiogenesis (11,12). The angiogenic functional difference may be due, at least in part, to N-terminal sequence differences. PF4 lacks the IL8 N-terminal tripeptide Glu-Leu-Arg (ELR) motif, which is known to mediate IL8 receptor binding and subsequent signal transduction (13). In additi...

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“…Heparin has been demonstrated to promote vascular cells proliferation and to enhance effects of various growth factors involved in the process of vascular growth as described above (Mueller et al 1989;Yamashita et al 1992;Toriyama et al 1997;Heaky et al 2000;Jesundason et al 2000;Norrby 2000). The potential contact between heparin and its cell surface receptor is considered a critical and initial step in these antiproliferative effects of heparin (Gupta et al 1994;Han et al 1997). In addition pharmacological effects of heparin have been considered mainly anticoagulant effects and angiogenesis through interactions with a family of polypeptide growth factor that stimulated endothelial cell proliferation (Garg et al 2000).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, heparin is also well-known to exert proliferative effects on vascular endothelial cells and at the same time anti-proliferative effects on vascular smooth muscle cells (SMC) (Gupta and Singh 1994;Han et al 1997). Protamine sulfate demonstrated antagonistic effects toward anticoagulant activity of heparin and is commonly employed to reverse the large heparin dosage usually required in cardiovascular surgical procedures (Taylor and Folkman 1982;Pearson et al 1992).…”

confidence: 99%

Heparin Accelerates Pulmonary Artery Development in Neonate Rabbits

Watanabe

Suzuki

Shizawa

et al. 2005

Tohoku J. Exp. Med.

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Pulmonary vascular resistance drops sharply within a few minutes after birth for the survival of neonates. A majority of this resistance is caused by "pulmonary vascular bed" or vessel lacking smooth muscle cells. Heparin is known to promote proliferation and development of endothelial cells and to subsequently decrease their overall vascular resistance, but its detailed features remained unknown. Therefore, in this study we treated neonatal rabbits with heparin, protamine (antagonist of heparin), or saline, and evaluated histopathological features of vascular endothelial cells using two different types of computer assisted image analysis, i.e., CAS200 and NIH image. These two systems detected the percentage of vascular endothelial area per fields (VA) and CD31-positive area per total area of tissue following subtraction of background stain. CD31 was used as an endothelial cell marker. Heparin treated rabbits were associated with significant decrement of pulmonary/systemic artery pressure (Pp/Ps) (21.0 ± 6.0%) compared to protamine (29.9 ± 6.1%) or saline (29.4 ± 3.0%) treated animals. The values of VA obtained by the two image analyses (CAS200 and NIH image) were significantly increased in heparin treated animals (38.4 ± 3.2% determined by CAS200 and 24.0 ± 1.3% by NIH image) compared to protamine (30.2 ± 3.9% and 19.2 ± 1.8%) or saline (33.2 ± 1.5% and 20.8 ± 3.8%) treated animals on 14th day of treatment. The present study indicates that heparin accelerates pulmonary vascular bed development probably by increasing the number and volume of endothelial cells, which subsequently contributes to the decrease in pulmonary vascular resistance. pulmonary artery vascular resistance; pulmonary vascular density; heparin; CD31; image analysis

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Inhibition of endothelial cell proliferation by platelet factor-4 involves a unique action on S phase progression.

Cited by 110 publications

References 30 publications

Serum protein signature may improve detection of ductal carcinoma in situ of the breast

Serum protein signature may improve detection of ductal carcinoma in situ of the breast

Platelet Factor 4 and Interleukin-8 CXC Chemokine Heterodimer Formation Modulates Function at the Quaternary Structural Level

Heparin Accelerates Pulmonary Artery Development in Neonate Rabbits

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