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Gene Review

Serpine2  -  serpin peptidase inhibitor, clade E (nexin...

Rattus norvegicus

Synonyms: GDN, Gdnpn1, Glia-derived nexin, PI-7, PN-1, ...
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Disease relevance of Serpine2

  • We show here that synthetic peptide inhibitors with thrombin specificity mimic GDN at similar concentrations in neuroblastoma cells [1].
  • In vitro CpG methylation blocked transcription from the GDN/PN-1 promoter in rat hepatoma cells but not in C6 rat glioma cells [2].
  • Using semi-quantitative reverse transcription-polymerase chain reaction analysis, we show that prothrombin was up-regulated in the hippocampal formation 24 h after transient global ischemia in rats (two-vessel occlusion with hypotension), whereas the expression of PN-1 and the expression of PAR-subtypes 1-3 did not change significantly [3].
  • These results further support the suggestion that GDN is important for axonal regeneration in vivo, and indicate that protease inhibitors could have a role in Wallerian degeneration and peripheral nerve regeneration [4].
  • Levels of both PN-1 and thrombin are increased in the brain in response to insults such as ischemia, suggesting roles in neural injury and repair processes [5].

High impact information on Serpine2

  • GDN can promote neurite outgrowth in vitro from neuroblastoma cells, sympathetic neurons and hippocampal neurons (L. Farmer et al., manuscript in preparation) [4].
  • Here we report that after lesion of the rat sciatic nerve there is a large transient increase in the amount of GDN messenger RNA and of released GDN [4].
  • Glia-derived nexin (GDN), also known as protease nexin I, is a serine protease inhibitor of deduced relative molecular mass 41,700, identified in conditioned media of glioma cells by its neurite-promoting activity [4].
  • A 1 min exposure of PC12 cells to interferon-gamma also causes PN1 gene induction, suggesting that the "triggered" NGF and interferon-gamma signaling pathways share common molecular intermediates [6].
  • Whereas continuous exposure to NGF causes the induction of a family of sodium channels, the effect of a brief exposure is to induce selectively expression of the peripheral nerve-type sodium channel gene PN1, through a distinct signaling pathway requiring immediate-early genes [6].

Chemical compound and disease context of Serpine2


Biological context of Serpine2

  • Point mutations in the E-box binding site which abolish USF binding in vitro increase the transcriptional activity of the PN-1 promoter [8].
  • A strong negative regulatory element has been shown by the missing nucleoside technique to be a CACGTG site (E-box) in the proximal part of the PN-1 promoter [8].
  • The 5'-flanking sequence and the first exon were found to be GC-rich, indicating that the 5' region of the rat GDN/PN-1 gene resides within a CpG island [2].
  • The presence of these consensus sequences is consistent with the known expression pattern of GDN/PN-1 [2].
  • The first three exons and the promoter of rat glia-derived nexin, also called protease nexin-1 (GDN/PN-1), have been identified through analysis of rat genomic clones [2].

Anatomical context of Serpine2

  • All of the effects of thrombin on astrocytes and neurons were blocked by the brain thrombin inhibitor, protease nexin-1 (PN-1) [9].
  • These results indicate that thrombin and PN-1 may regulate the viability of both astrocytes and neurons in early moments following trauma to the CNS or other conditions that alter the blood-brain barrier [9].
  • The expression of the serine protease inhibitor Protease nexin-1 (PN-1) is upregulated in glial cells following different types of lesion in the nervous system [8].
  • In chick sympathetic neurons, GDN but not hirudin and synthetic peptide inhibitors promoted neurite outgrowth (Zurn et al., 1988) [1].
  • We examined the effect of thrombin on PN-1 expression by rat aortic smooth muscle cells (RASMCs) [10].

Associations of Serpine2 with chemical compounds

  • A lower amount of PN-1 was released by heparin from TRAP-stimulated versus unstimulated cells and correlated with a decreased capacity to inhibit thrombin [10].
  • Protease nexin-1 (PN-1), a potent inhibitor of serine proteases, is present in vascular cells and forms complexes with thrombin, plasminogen activators, and plasmin [10].
  • Pre-treatment of smooth muscle cells with cycloheximide abolished the reduction of PN-1 expression by thrombin [10].
  • These antibodies stain a single band at 43 kd on immunoblots of concentrated C6 glioma-conditioned medium and have been used to demonstrate that GDN is present in the olfactory system of the rat [11].
  • Displacement of Ang II binding using the selective ligands losartan and CGP 42112 led to a severalfold increase of PN-1 protein and mRNA over basal levels, indicating that the observed effect was mediated by specific binding sites [12].

Regulatory relationships of Serpine2

  • This effect was mediated via the interaction of thrombin with its receptor protease activated receptor (PAR-1) since the peptide thrombin receptor activating peptide (TRAP) reduced PN-1 expression [10].

Other interactions of Serpine2


Analytical, diagnostic and therapeutic context of Serpine2


  1. Functional sites of glia-derived nexin (GDN): importance of the site reacting with the protease. Nick, H., Hofsteenge, J., Shaw, E., Rovelli, G., Monard, D. Biochemistry (1990) [Pubmed]
  2. Molecular organization of the rat glia-derived nexin/protease nexin-1 promoter. Ernø, H., Monard, D. Gene Expr. (1993) [Pubmed]
  3. Increase of prothrombin-mRNA after global cerebral ischemia in rats, with constant expression of protease nexin-1 and protease-activated receptors. Riek-Burchardt, M., Striggow, F., Henrich-Noack, P., Reiser, G., Reymann, K.G. Neurosci. Lett. (2002) [Pubmed]
  4. Induction of glia-derived nexin after lesion of a peripheral nerve. Meier, R., Spreyer, P., Ortmann, R., Harel, A., Monard, D. Nature (1989) [Pubmed]
  5. Protease nexin-1 and thrombin modulate neuronal Ca2+ homeostasis and sensitivity to glucose deprivation-induced injury. Smith-Swintosky, V.L., Zimmer, S., Fenton, J.W., Mattson, M.P. J. Neurosci. (1995) [Pubmed]
  6. A single pulse of nerve growth factor triggers long-term neuronal excitability through sodium channel gene induction. Toledo-Aral, J.J., Brehm, P., Halegoua, S., Mandel, G. Neuron (1995) [Pubmed]
  7. Synthesis of glia-derived nexin in yeast. Sommer, J., Meyhack, B., Rovelli, G., Buergi, R., Monard, D. Gene (1989) [Pubmed]
  8. Excitotoxic brain lesion modifies binding to a USF binding site acting as a negative regulatory element in the Protease nexin-1 promoter. Ernø, H., Küry, P., Nitsch, C., Jost, J.P., Monard, D. Mol. Cell. Neurosci. (1996) [Pubmed]
  9. Thrombin receptor activation protects neurons and astrocytes from cell death produced by environmental insults. Vaughan, P.J., Pike, C.J., Cotman, C.W., Cunningham, D.D. J. Neurosci. (1995) [Pubmed]
  10. Protease nexin-1: a cellular serpin down-regulated by thrombin in rat aortic smooth muscle cells. Richard, B., Arocas, V., Guillin, M.C., Michel, J.B., Jandrot-Perrus, M., Bouton, M.C. J. Cell. Physiol. (2004) [Pubmed]
  11. Detection of glia-derived nexin in the olfactory system of the rat. Reinhard, E., Meier, R., Halfter, W., Rovelli, G., Monard, D. Neuron (1988) [Pubmed]
  12. Regulation of protease nexin-1 expression in cultured Schwann cells is mediated by angiotensin II receptors. Bleuel, A., de Gasparo, M., Whitebread, S., Püttner, I., Monard, D. J. Neurosci. (1995) [Pubmed]
  13. Changes in the expression of protease-activated receptor 1 and protease nexin-1 mRNA during rat nervous system development and after nerve lesion. Niclou, S.P., Suidan, H.S., Pavlik, A., Vejsada, R., Monard, D. Eur. J. Neurosci. (1998) [Pubmed]
  14. Differentially expressed genes in hippocampal cell cultures in response to an excitotoxic insult by quinolinic acid. Seidel, B., Keilhoff, G., Reinheckel, T., Wolf, G. Brain Res. Mol. Brain Res. (1998) [Pubmed]
  15. Protease nexin-1 is expressed at the mouse met-/mesencephalic junction and FGF signaling regulates its promoter activity in primary met-/mesencephalic cells. Küry, P., Schaeren-Wiemers, N., Monard, D. Development (1997) [Pubmed]
  16. Ontogeny of water transport in rat brain: postnatal expression of the aquaporin-4 water channel. Wen, H., Nagelhus, E.A., Amiry-Moghaddam, M., Agre, P., Ottersen, O.P., Nielsen, S. Eur. J. Neurosci. (1999) [Pubmed]
  17. Age-dependent effects of gestational and lactational iron deficiency on anxiety behavior in rats. Eseh, R., Zimmerberg, B. Behav. Brain Res. (2005) [Pubmed]
  18. Sex differences in Fos protein expression in the neonatal rat brain. Olesen, K.M., Auger, A.P. J. Neuroendocrinol. (2005) [Pubmed]
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