Regulation of Inducible Heparanase Gene Transcription in Activated T Cells by Early Growth Response 1

Abstract

Cleavage of heparan sulfate by the β-d-endoglucuronidase heparanase (HPSE) is a fundamental event in a number of important physiological processes including inflammation, wound healing, and angiogenesis. HPSE activity has also been directly correlated with pathological conditions such as tumor growth and metastasis and autoimmune disease. The tight regulation of HPSE expression and function is critical to ensure homeostasis of the normal physiological processes to which it contributes and to prevent imbalance toward pathological situations. Little is known about the transcriptional mechanisms that regulate HPSE expression. In this study we have shown human HPSE gene transcription in Jurkat T cells is induced upon activation. Functional analysis of the HPSE promoter has identified a 280-bp region that is highly inducible. Mutation studies together with supershift experiments have identified a 4-bp motif that binds the transcription factor early growth response-1 (Egr1) and is critical in regulating inducible HPSE gene transcription. Furthermore, the overexpression of Egr1 resulted in the enhanced activation of the HPSE promoter. By using MAPK pathway inhibitors, we have also shown that inducible expression of HPSE mRNA and the activity of the 280-bp HPSE promoter element are dependent on the ERK1/2 (MEK1/2) pathway. This pathway is critical for induction of Egr1 expression at both the mRNA and protein level in T cells, an observation that provides further support to Egr1 playing an important role as a key activator of HPSE expression. In addition, HPSE and Egr1 were shown to co-localize by immunohistochemistry to invading mononuclear leukocytes in actively induced experimental autoimmune encephalomyelitis in rats. These findings provide the first insight into the mechanisms controlling inducible transcription of the HPSE gene, and could represent an important lead into understanding how HPSE expression is deregulated in metastatic tumor cells. Cleavage of heparan sulfate by the β-d-endoglucuronidase heparanase (HPSE) is a fundamental event in a number of important physiological processes including inflammation, wound healing, and angiogenesis. HPSE activity has also been directly correlated with pathological conditions such as tumor growth and metastasis and autoimmune disease. The tight regulation of HPSE expression and function is critical to ensure homeostasis of the normal physiological processes to which it contributes and to prevent imbalance toward pathological situations. Little is known about the transcriptional mechanisms that regulate HPSE expression. In this study we have shown human HPSE gene transcription in Jurkat T cells is induced upon activation. Functional analysis of the HPSE promoter has identified a 280-bp region that is highly inducible. Mutation studies together with supershift experiments have identified a 4-bp motif that binds the transcription factor early growth response-1 (Egr1) and is critical in regulating inducible HPSE gene transcription. Furthermore, the overexpression of Egr1 resulted in the enhanced activation of the HPSE promoter. By using MAPK pathway inhibitors, we have also shown that inducible expression of HPSE mRNA and the activity of the 280-bp HPSE promoter element are dependent on the ERK1/2 (MEK1/2) pathway. This pathway is critical for induction of Egr1 expression at both the mRNA and protein level in T cells, an observation that provides further support to Egr1 playing an important role as a key activator of HPSE expression. In addition, HPSE and Egr1 were shown to co-localize by immunohistochemistry to invading mononuclear leukocytes in actively induced experimental autoimmune encephalomyelitis in rats. These findings provide the first insight into the mechanisms controlling inducible transcription of the HPSE gene, and could represent an important lead into understanding how HPSE expression is deregulated in metastatic tumor cells. Heparan sulfate proteoglycans are key structural components of the extracellular matrix (ECM) 1The abbreviations used are: ECMextracellular matrixHPSEheparanaseEgr1early growth response geneEAEexperimental autoimmune encephalomyelitisEMSAelectrophoretic mobility shift assayHSheparan sulfatePMAphorbol 12-myristate-13 acetateIOcalcium ionophoreUBCubiquitin-conjugating enzyme E2D2USunstimulatedMAPKmitogen-activated protein kinaseERKextracellular signal-regulated kinaseMEKMAPK/ERK kinaseRT-PCRreverse transcriptase-PCRRACErapid amplification of cDNA ends. and cell surfaces. They comprise a protein core covalently linked to linear chains of the complex sulfated glycosaminoglycan, heparan sulfate (HS) (1.Kjellen L. Lindahl U. Annu. Rev. Biochem. 1991; 60: 443-475Crossref PubMed Scopus (1690) Google Scholar, 2.Yanagishita M. Hascall V.C. J. Biol. Chem. 1992; 267: 9451-9454Abstract Full Text PDF PubMed Google Scholar, 3.Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2356) Google Scholar). The HS side chains of heparan sulfate proteoglycans mediate the assembly and stability of the ECM through interactions with the various matrix components (e.g. collagen, laminin, and fibronectin) (1.Kjellen L. Lindahl U. Annu. Rev. Biochem. 1991; 60: 443-475Crossref PubMed Scopus (1690) Google Scholar, 3.Bernfield M. Gotte M. Park P.W. Reizes O. Fitzgerald M.L. Lincecum J. Zako M. Annu. Rev. Biochem. 1999; 68: 729-777Crossref PubMed Scopus (2356) Google Scholar) and also specifically bind a range of cytokines and growth factors (e.g. basic fibroblast growth factor, hepatocyte growth factor, insulin-like growth factor, and transforming growth factor-β) thereby functioning as a storage depot for these factors (4.Vlodavsky I. Bar-Shavit R. Korner G. Fuks Z. Rohrbach D.H. Timple R. Basement Membranes: Cellular and Molecular Aspects. Academic Press, Orlando1993: 327-343Google Scholar, 5.Taipale J. Keski-Oja J. FASEB J. 1997; 11: 51-59Crossref PubMed Scopus (774) Google Scholar). The β-d-endoglycosidase heparanase (HPSE) cleaves HS and facilitates the degradation of the ECM and the release of HS-bound growth factors (6.Vlodavsky I. Friedmann Y. J. Clin. Investig. 2001; 108: 341-347Crossref PubMed Scopus (554) Google Scholar, 7.Parish C.R. Freeman C. Hulett M.D. Biochim. Biophys. Acta. 2001; 1471: M99-M108PubMed Google Scholar). Heparanase is a normal constituent of activated leukocytes, endothelial cells, vascular smooth muscle cells, and cytotrophoblasts; however, its expression is also “hijacked” by metastatic tumor cells (6.Vlodavsky I. Friedmann Y. J. Clin. Investig. 2001; 108: 341-347Crossref PubMed Scopus (554) Google Scholar, 7.Parish C.R. Freeman C. Hulett M.D. Biochim. Biophys. Acta. 2001; 1471: M99-M108PubMed Google Scholar). The level of HPSE activity expressed by many of these cell types correlates with their activated or invasive states, and as such HPSE has been implicated in many important physiological and pathological processes, including inflammation, wound healing, embryonic development, angiogenesis, and metastasis (6.Vlodavsky I. Friedmann Y. J. Clin. Investig. 2001; 108: 341-347Crossref PubMed Scopus (554) Google Scholar, 7.Parish C.R. Freeman C. Hulett M.D. Biochim. Biophys. Acta. 2001; 1471: M99-M108PubMed Google Scholar). Indeed, substantial evidence has been generated using HPSE inhibitor studies (8.Parish C.R. Freeman C. Brown K.J. Francis D.J. Cowden W.B. Cancer Res. 1999; 59: 3433-3441PubMed Google Scholar, 9.Vlodavsky I. Mohsen M. Lider O. Svahn C.M. Ekre H.P. Vigoda M. Ishai-Michaeli R. Peretz T. Invasion Metastasis. 1994; 14: 290-302PubMed Google Scholar, 10.Irony-Tur-Sinai M. Vlodavsky I. Ben-Sasson S.A. C. T. J. Full Text Full Text PDF PubMed Scopus Google Scholar) and with using HPSE I. Friedmann Y. M. R. Ishai-Michaeli R. M. O. Peretz T. I. L. I. 1999; PubMed Scopus Google or cDNA T. Y. M. T. Y. M. Cancer Res. 2001; Google that a HPSE expression and experimental autoimmune or Furthermore, a level of HPSE mRNA or protein expression has been shown to with tumor and metastasis Cancer PubMed Scopus Google Scholar, J. I. Vlodavsky I. Cancer Res. 2001; Google Scholar, Y. Vlodavsky I. Peretz T. I. O. J. Full Text Full Text PDF PubMed Scopus Google Scholar) and a of M. M. J. Y. M. J. 2001; PubMed Scopus Google Scholar, M. Y. T. Y. T. M. M. M. Investig. PubMed Scopus Google Scholar). These findings that HPSE an important role in the of leukocytes to and also in tumor and extracellular matrix heparanase early growth response gene experimental autoimmune encephalomyelitis mobility shift heparan sulfate 12-myristate-13 enzyme protein extracellular signal-regulated amplification of cDNA ends. The of various cell types in a number of to the and of a gene HPSE activity I. Friedmann Y. M. R. Ishai-Michaeli R. M. O. Peretz T. I. L. I. 1999; PubMed Scopus Google Scholar, M.D. Freeman C. C.R. 1999; PubMed Scopus Google Scholar, M. M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, PubMed Scopus Google Scholar). This evidence to that the enzyme is the enzyme in and the that it a highly HPSE is expressed as a and is to an enzyme that has been to a of an and a the and I. Friedmann Y. M. R. Ishai-Michaeli R. M. O. Peretz T. I. L. I. 1999; PubMed Scopus Google Scholar, M.D. Freeman C. C.R. 1999; PubMed Scopus Google Scholar, J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. M. R. G. R. J. M. R. C. Biochem. J. PubMed Scopus Google Scholar). analysis of the human enzyme has it is a of the a with a that is dependent on a at and a at M.D. J. Freeman C. C.R. PubMed Scopus Google Scholar). gene at HPSE I. Friedmann Y. M. R. Ishai-Michaeli R. M. O. Peretz T. I. L. I. 1999; PubMed Scopus Google Scholar, J. Freeman C. C.R. Hulett M.D. Res. 1999; PubMed Scopus Google Scholar, J. M. M. PubMed Scopus Google Scholar). analysis has identified HPSE mRNA a mRNA expressed in and and a mRNA that is also expressed at in M.D. Freeman C. C.R. 1999; PubMed Scopus Google Scholar, Biochem. Biophys. Res. 1999; PubMed Scopus Google Scholar). The tight regulation of HPSE function is of critical in homeostasis of the normal physiological processes in which it is T cells have been shown to of HPSE activity upon activation are to to a of I. Y. Ishai-Michaeli R. Lider O. Y. Fuks Z. Invasion Metastasis. 1992; Google Scholar, Y. Fuks Z. Vlodavsky I. PubMed Scopus Google Scholar, R. Lider O. Y. Fuks Z. Vlodavsky I. J. PubMed Scopus Google Scholar). number of of of HPSE function are including regulation at the transcriptional as as in the and activity of the have been in understanding the of the I. Friedmann Y. M. R. Ishai-Michaeli R. M. O. Peretz T. I. L. I. 1999; PubMed Scopus Google Scholar, M.D. Freeman C. C.R. 1999; PubMed Scopus Google Scholar, J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. J. M. R. G. R. J. M. R. C. Biochem. J. PubMed Scopus Google Scholar) and also the and that its activity O. L. C. Vlodavsky I. Res. PubMed Scopus Google Scholar, K.J. J. PubMed Scopus Google Scholar, L. O. I. Vlodavsky I. J. PubMed Google Scholar). In is known of the mechanisms that HPSE gene transcription. it that transcription factors of the and a role in controlling the activity of human HPSE gene expression PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is known about the mechanisms that regulate inducible transcription of the HPSE In this study we have shown that human HPSE transcription is induced upon activation of T cells. Furthermore, we have the HPSE promoter in T cells and identified the transcription factor early growth response-1 (Egr1) as critical in to a element in the HPSE promoter and regulating inducible transcription. amplification of cDNA on human cDNA to the with the human and and T cells were in with in a of were using at and with of cells. the a of of were the by using the cells were for and with and were by of and of protein used for to a L. Scholar). using a of the human HPSE gene promoter and were by human that been using as the and or and were used to the or and were used to the using the as a The used are as and The or were into the or in the of to the and The with to the of the and to the a promoter The Egr1 generated by by the core of the motif to using the as a were to and which were together in a The used to these were and or and The of and were and The of by using an The expression and the were of on Jurkat T cells that were with and for or or with G. or both for to and used to Egr1 and in using Egr1 or the 1999; PubMed Scopus Google Scholar). using and Jurkat T cells that were or with and using as by the of used for cDNA using a first cDNA as the were using a in a of to the amplification of HPSE or Egr1 were to prevent amplification of and conditions were and the used for the for by of for for and for The of used for of HPSE cDNA were and and for the Egr1 cDNA were and to a generated for both HPSE and Egr1 using known of a the cDNA to the This used to the of the to number of of also using the to enzyme This used for the for in and cDNA as the expression of mRNA to upon Jurkat T cell in to the expression of such as and which in The used to cDNA are and and T cells with or both were and in of as J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). were for at with to of in a of and of In of or were with the for to the of the The were on a and The of T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and are and of and were with of basic protein in as M. J. Google Scholar). the of were in with were for or for using HPSE of Egr1 or the human M.D. J. C.R. Biochem. Biophys. Res. 2001; PubMed Scopus Google using the were with HPSE by and this study we Jurkat T cells as a cell to the inducible expression of human The used to the T cells were and that transcription factors of T cell activation. In HPSE mRNA expression in activated Jurkat T cells using Jurkat T cells were or with and for and HPSE mRNA were with cells at and at This in HPSE mRNA expression correlates with the HPSE activity in T cells activated Y. Fuks Z. Vlodavsky I. PubMed Scopus Google Scholar). of an analysis of the human HPSE promoter to the of inducible transcriptional regulation of the HPSE used to the transcription of the HPSE gene in human using the HPSE and on human cDNA a of a transcription at of the This is with that for the transcription of the HPSE gene in tumor cell I. Friedmann Y. M. R. Ishai-Michaeli R. M. O. Peretz T. I. L. I. 1999; PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). of the promoter to the transcription and were human and into the and analysis to the to activity and the of cells with and for for studies as HPSE mRNA expression is induced and activity highly expressed these By using this the 280-bp inducible activity as to the and which inducible activity This that the region at the of the 280-bp to a element that inducible transcription of the HPSE Mutation of the Egr1 analysis of the to HPSE promoter region using T. Res. PubMed Scopus Google Scholar) a number of transcription factor which and that have been shown to a role in expression of HPSE In addition, a early growth response gene identified as a for playing a role in the regulation of inducible HPSE gene expression. the for inducible promoter a of the motif core in the 280-bp promoter and analysis of Jurkat cells with and for the inducible transcriptional activity of the by with the In addition, of expression also by the These that the motif is critical to transcriptional regulation of the HPSE gene in Jurkat T cells and that Egr1 an important Egr1 the HPSE shift analysis to Egr1 to bind to the element identified we of Jurkat T cells expressed Egr1 that of a Egr1 Jurkat T cells were with and an and studies were inducible complex as early as and at this complex at The of the complex by its supershift by using an The of these with the level of protein expression of Egr1 in as by it is dependent on the of Egr1 protein in the The complex is and the complex is as the HPSE Egr1 mRNA are upon with and as using Jurkat T cells or for and cDNA of and to The were to mRNA number by using a and the induction expressed as the in number to cells. The represent the of analysis using an Egr1 on Jurkat T cells or with or or both for and to the of an Egr1 expression with HPSE promoter of with of Egr1 expression and the of into Jurkat T cells which were with and for and analysis in and the are of The activity of the Egr1 cells are to with the These studies were to the the HPSE promoter that the with Jurkat T cells or with for inducible complex with the which to Egr1 by supershift This supershift the with the The core of the in the HPSE by to in to the of this element for Egr1 Egr1 complex with the that the for the core were for with these provide evidence to that Egr1 bind the in the HPSE promoter and that the is as it is cell activation. The also resulted in of of The and and are as The complex is by the it binds through an on the Egr1 the HPSE expression at the level of both mRNA and protein in Jurkat T cells to this transcription factor inducible the experimental conditions of cell activation used in this Egr1 mRNA were by and to by analysis that induction of Egr1 protein by or and as early as and at with expression at of Egr1 expression used with the induction to or a the The overexpression of Egr1 by of the Egr1 expression with the into Jurkat T cells to the of Egr1 to HPSE transcriptional of were with into Jurkat T cells and of of the Egr1 expression a in activity of to with the HPSE on the inhibitor and the MAPK inhibitor were used in analysis studies to provide insight into the for inducible HPSE transcription. studies in cell types have shown the expression of Egr1 is dependent on the the MAPK and this is by of cells to for to for resulted in a in the inducible activity of the 280-bp HPSE promoter region an that of cells to for to for resulted in of inhibitor a on the These that inducible HPSE transcription is dependent on the the MAPK pathway a used to the of these at the level of HPSE and Egr1 gene expression. HPSE mRNA by by The level of of cells to both and to that with is regulating HPSE expression both are used This observation is with the of inducible transcription of the 280-bp HPSE promoter region with both and and that the pathway a role in HPSE expression. Egr1 expression at the level of mRNA and protein the conditions to the for its expression in Jurkat T cells. Egr1 mRNA by by the level of of cells with both and to that with The of the and on Egr1 protein expression by analysis of Jurkat T cells with and expression in by by This is with the expression of Egr1 at the mRNA level expression as a These Egr1 expression is by the a that is with experiments on cell HPSE and Egr1 to in the expression of both HPSE and Egr1 in an in of T immunohistochemistry on of of in which been actively is a autoimmune of the and an of the M. J. Google Scholar). for HPSE or Egr1 of expression in mononuclear cells in the and of the and Egr1 expression also in endothelial cells the with a to HPSE is a normal constituent of leukocytes it has been implicated in cell to of I. Y. Ishai-Michaeli R. Lider O. Y. Fuks Z. Invasion Metastasis. 1992; Google Scholar). The regulation of HPSE expression and activity in leukocytes to to prevent HS degradation that in HPSE activity is with leukocytes in their activated This has been in T cells, which have of HPSE activity activated in their I. Y. Ishai-Michaeli R. Lider O. Y. Fuks Z. Invasion Metastasis. 1992; Google Scholar). The of HPSE activity in activated T cells has been with autoimmune such as 2001; Scholar) and experimental autoimmune encephalomyelitis M. Vlodavsky I. Ben-Sasson S.A. C. T. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Indeed, of HPSE has been shown to the of these M. Vlodavsky I. Ben-Sasson S.A. C. T. J. Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, of HPSE activity is also induced upon activation of cells such as endothelial cells and smooth muscle cells PubMed Scopus Google Scholar, C. C.R. Biochem. J. 1997; PubMed Scopus Google Scholar, M. 1999; Full Text Full Text PDF PubMed Scopus Google the of controlling HPSE the expression of HPSE by these cell types has been linked with and D.J. C.R. M. Brown K.J. Cowden W.B. Res. PubMed Google Scholar). studies Cancer PubMed Scopus Google Scholar, J. I. Vlodavsky I. Cancer Res. 2001; Google Scholar) in tumor cells have that of in highly directly with of HPSE This that the of HPSE expression at the transcriptional level is important in regulating HPSE The of HPSE gene transcription is and is known of the mechanisms that lead to inducible transcription. In this by using the Jurkat T cell as a we have that HPSE gene transcription is induced upon activation and have identified an inducible element in the HPSE promoter. we have shown that the transcription factor Egr1 specifically bind to this and HPSE transcription upon cell activation. This is the first of the transcriptional mechanisms inducible regulation of the HPSE Egr1 is a transcription factor also known as or T. PubMed Scopus Google Scholar, S.A. T. Full Text PDF PubMed Scopus Google Scholar). has been as a key transcription factor induced upon activation of smooth muscle cells T. J. 1997; PubMed Google Scholar) and endothelial cells T. PubMed Scopus Google Scholar). have shown that is also induced in T cells upon activation with and The role of Egr1 in T cells is however, it has been to as a of expression R. J. J. 2001; PubMed Scopus Google Scholar) and M. S.A. J. PubMed Scopus Google Scholar). the Egr1 promoter is activated by T cell J. PubMed Scopus Google and Egr1 gene expression of T Biol. PubMed Scopus Google that support a role for transcription of in activated T cells. have that and of the in the HPSE promoter in of inducible promoter of an Egr1 expression together with an HPSE promoter resulted in promoter Furthermore, the of Egr1 with the motif in the HPSE promoter is dependent on the of the as shown by These provide evidence to that Egr1 an important role in regulating inducible HPSE gene transcription. mechanisms controlling expression of HPSE gene transcription in tumor cells have been promoter region to has been identified as for expression of HPSE in tumor cells J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is a transcription factor shown G. 1999; PubMed Scopus Google Scholar) to a role in transcription of many of the are in the 280-bp HPSE promoter used in transcriptional regulation cell a as a of HPSE in experimental studies on regulation of in T cells, it that has been shown to bind Egr1 R. J. Biol. Chem. Full Text PDF PubMed Google Scholar). such it to that studies of the core in the 280-bp HPSE promoter resulted in the of inducible transcription also in the of The region to for both Egr1 and have shown this region binds and we that it also binds in T cell In support of the complex in studies in cell is to as it has been shown that binds to this of the HPSE promoter in tumor cells J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the complex is the motif is and studies using a in have identified a complex that J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google and this complex a mobility to the complex identified in has been shown to with Egr1 for to promoter have the of by Egr1 at an in vascular T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, T. PubMed Scopus Google Scholar). have to the of this on the HPSE promoter upon activation of T cells. studies are to this studies have transcription factors as of HPSE expression in tumor cell The first of these studies the for a and the in to a number of in the to region and controlling transcription of HPSE in tumor J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). study has an of the promoter and that these were important in and and regulating HPSE expression in metastatic tumor cells PubMed Scopus Google Scholar). the transcription factors also have a role in regulating HPSE transcription in leukocytes to studies have on factors for induction of HPSE gene of the promoter also a region at to that The of in the HPSE promoter that could HPSE gene transcription is of of the in the studies of PubMed Scopus Google Scholar) and J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) also the of in the HPSE at to and to These are of that identified however, the studies were in or tumor cell and could in HPSE gene regulation these cells and analysis of the to region of the HPSE promoter has for transcription factors with including and The role of these in regulating HPSE transcription is of T including the MAPK that the cell to the used to MAPK to that induction of HPSE and Egr1 expression in T cells. is an inhibitor that binds and of in of induction of the ERK1/2 (MEK1/2) pathway. studies of the HPSE promoter using have shown inducible HPSE transcription to dependent on this pathway. to the induction of Egr1 mRNA and protein in Jurkat T cells to dependent on the ERK1/2 a with studies M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) in cell the ERK1/2 pathway Rev. Biol. PubMed Scopus Google these inhibitor are into the of and studies on the HPSE are highly that the ERK1/2 pathway HPSE expression through its regulation of The of Egr1 in regulating inducible HPSE transcription in T cells that Egr1 is to have a role in T in which HPSE expression has been Indeed, of the expression of HPSE and Egr1 by immunohistochemistry in of actively induced as in this study have that HPSE and Egr1 are by the invading mononuclear leukocytes for the of to Egr1 is also regulating the inducible transcription of HPSE in and of that to cell in These studies provide the first insight into inducible regulation of HPSE at the level of transcription. is that these mechanisms are cell to T cells also a of cells in which HPSE expression is HPSE expression is inducible in cells such as endothelial cells and smooth muscle cells PubMed Scopus Google Scholar, C. C.R. Biochem. J. 1997; PubMed Scopus Google Scholar, M. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Egr1 expression is in these cell types T. PubMed Scopus Google Scholar, T. J. 1997; PubMed Google Scholar) it inducible expression of a number of including growth and factor, transforming growth and T. PubMed Scopus Google Scholar, J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). it is to that the vascular endothelial cells in the in this study were to HPSE This that HPSE expression in endothelial cells in by a Furthermore, studies of the role of Egr1 in tumor cell metastasis and are have been studies that Egr1 expression with tumor Biol. PubMed Scopus Google Scholar, S.A. Z. J. J. 2001; PubMed Scopus Google Scholar). the overexpression of HPSE in various invasive is to a of it of to Egr1 is a key factor to the level of HPSE expression in metastatic tumor cells. C. R. for critical of the for the of the and for with the