The ERK/MAPK Pathway Regulates the Activity of the Human Tissue Factor Pathway Inhibitor-2 Promoter

Human tissue factor pathway inhibitor-2 (hTFPI-2) is a 32-kDa serine protease inhibitor that is associated with the extracellular matrix. hTFPI-2 inhibits several extracellular matrix-degrading serine proteases and may play a role in tumor invasion and metastasis. To study the signal transduction pathway that leads to the activation of the hTFPI-2, we cloned the potential promoter region of this gene adjacent to a heterologous luciferase reporter gene. Phorbol 12-myristate 13-acetate (PMA) induced the luciferase reporter gene in HEK293 cells and other epithelial cell lines, such as the human lung carcinoma A549 cells, the breast carcinoma MCF7 cells, and the cervical HeLa cells. This PMA induction was blocked with the MEK inhibitor UO126, suggesting that the PMA-induced activation of the hTFPI-2 promoter is mediated through MEK. Furthermore, epidermal growth factor induced the luciferase reporter gene in HeLa cells. Cotransfection of the luciferase construct with constitutively active components of the Ras/Raf/MEK/ERK pathway in EcR-293 cells lead to a 7- to 92-fold induction of the luciferase reporter gene, indicating that regulation of hTFPI-2 is mediated through this pathway. A series of luciferase reporter gene constructs with progressive deletions of the 5′-flanking region suggested that the minimal basal promoter activity is located between nucleotide positions −89 and −384, whereas the minimal inducible promoter activity is between −89 and −222. We have used the computer program TFSEARCH and mutagenesis to analyze potential transcription factor binding sites. We identified an AP-1 binding site at nucleotide position −156 (inducible activity) and a Sp1 site at position −134 (basal activity) as potential cis-acting elements in the promoter region of the hTFPI-2. Human tissue factor pathway inhibitor-2 (hTFPI-2) is a 32-kDa serine protease inhibitor that is associated with the extracellular matrix. hTFPI-2 inhibits several extracellular matrix-degrading serine proteases and may play a role in tumor invasion and metastasis. To study the signal transduction pathway that leads to the activation of the hTFPI-2, we cloned the potential promoter region of this gene adjacent to a heterologous luciferase reporter gene. Phorbol 12-myristate 13-acetate (PMA) induced the luciferase reporter gene in HEK293 cells and other epithelial cell lines, such as the human lung carcinoma A549 cells, the breast carcinoma MCF7 cells, and the cervical HeLa cells. This PMA induction was blocked with the MEK inhibitor UO126, suggesting that the PMA-induced activation of the hTFPI-2 promoter is mediated through MEK. Furthermore, epidermal growth factor induced the luciferase reporter gene in HeLa cells. Cotransfection of the luciferase construct with constitutively active components of the Ras/Raf/MEK/ERK pathway in EcR-293 cells lead to a 7- to 92-fold induction of the luciferase reporter gene, indicating that regulation of hTFPI-2 is mediated through this pathway. A series of luciferase reporter gene constructs with progressive deletions of the 5′-flanking region suggested that the minimal basal promoter activity is located between nucleotide positions −89 and −384, whereas the minimal inducible promoter activity is between −89 and −222. We have used the computer program TFSEARCH and mutagenesis to analyze potential transcription factor binding sites. We identified an AP-1 binding site at nucleotide position −156 (inducible activity) and a Sp1 site at position −134 (basal activity) as potential cis-acting elements in the promoter region of the hTFPI-2. phorbol 12-myristate 13-acetate activating protein-1 Dulbecco's modified Eagle's medium epidermal growth factor extracellular signal regulated kinase human tissue factor inhibitor-2 mitogen-activated protein kinase MAPK/ERK kinase MEK kinase phosphate-buffered saline protein kinase C c-Jun amino-terminal kinase stress-activated protein kinase cytomegalovirus green fluorescence protein matrix metalloprotease Growth hormones and the tumor promoting agent PMA1 initiate diverse intracellular signaling pathways that lead to the phosphorylation of transcription factors and ultimately to the regulation of target genes. Among the pathways often used to transduce signals are the mitogen-activated protein kinase (MAPK) cascades. These cascades consist of a three-kinase module that includes an MEK kinase (MEKK), which activates an MAPK/ERK kinase (MEK), which in turn activates a MAPK (1Robinson M.J. Cobb M.H. Curr. Opin. Cell Biol. 1997; 9: 180-186Crossref PubMed Scopus (2286) Google Scholar). Three well characterized MAPKs have been described in mammalian cells: the mitogen-responsive ERK, the stress-responsive JNK/SAPK, and the p38 MAPK. The Ras/Raf/MEK/ERK signaling cascade regulates cell proliferation and differentiation (2Khosravi-Far R. Campbell S. Rossman K.L. Der C.J. Adv. Cancer Res. 1998; 72: 57-107Crossref PubMed Google Scholar). Components of this pathway are often activated in human tumors and oncogenic Ras, and constitutively activated ERKs have been found in a large variety of malignancies (3Shapiro P. Crit. Rev. Clin. Lab. Sci. 2002; 39: 285-330Crossref PubMed Scopus (86) Google Scholar, 4Sivaraman V.S. Wang H. Nuovo G.J. Malbon C.C. J. Clin. Invest. 1997; 99: 1478-1483Crossref PubMed Scopus (419) Google Scholar, 5Oka H. Chatani Y. Hoshino R. Ogawa O. Kakehi Y. Terachi T. Okada Y. Kawaichi M. Kohno M. Yoshida O. Cancer Res. 1995; 55: 4182-4187PubMed Google Scholar). We have used transcript profiling to identify genes that are differentially regulated by this pathway. Among the many activated genes, we have identified the human tissue factor pathway inhibitor-2 (hTFPI-2) as a gene that is highly up-regulated by the ERK/MAPK pathway. hTFPI-2 is a 32-kDa serine proteinase inhibitor with three tandem Kunitz-type domains (6Sprecher C.A. Kisiel W. Mathewes S. Foster D.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 3353-3357Crossref PubMed Scopus (185) Google Scholar, 7Miyagi Y. Koshikawa N. Yasumitsu H. Miyagi E. Hirahara F. Aoki I. Misugi K. Umeda M. Miyazaki K. J. Biochem. (Tokyo). 1994; 116: 939-942Crossref PubMed Scopus (95) Google Scholar) and has high homology to hTFPI-1, a regulator of the extrinsic blood coagulation pathway. The second Kunitz-type domain of hTFPI-1 binds to factor Xa, and this complex inhibits the activity of the factor VIIa-tissue factor complex through interaction of the first Kunitz-type domain in hTFPI-1 and the active site of VIIa/TF (8Girard T.J. Warren L.A. Novotny W.F. Likert K.M. Brown S.G. Miletich J.P. Broze Jr., G.J. Nature. 1989; 338: 518-520Crossref PubMed Scopus (429) Google Scholar). Despite the high homology of hTFPI-2 to hTFPI-1, hTFPI-2 is a weak inhibitor of the activation of factor X (9Petersen L.C. Sprecher C.A. Foster D.C. Blumberg H. Hamamoto T. Kisiel W. Biochemistry. 1996; 35: 266-272Crossref PubMed Scopus (139) Google Scholar) and hTFPI-2 poorly inhibits tissue factor. However, hTFPI-2 inhibits the tissue factor-factor VIIa complex and a variety of serine proteases, including trypsin, plasmin, plasma kallikrein, chymotrypsin, and cathepsin G, but it does not inhibit thrombin, urokinase-type plasminogen activator, and tissue-type plasminogen activator (6Sprecher C.A. Kisiel W. Mathewes S. Foster D.C. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 3353-3357Crossref PubMed Scopus (185) Google Scholar, 9Petersen L.C. Sprecher C.A. Foster D.C. Blumberg H. Hamamoto T. Kisiel W. Biochemistry. 1996; 35: 266-272Crossref PubMed Scopus (139) Google Scholar). Most of the hTFPI-2 expressed in dermal fibroblasts and endothelial cells localizes within the extracellular matrix, probably bound to heparan sulfate (10Rao C.N. Liu Y.Y. Peavey C.L. Woodley D.T. Arch. Biochem. Biophys. 1995; 317: 311-314Crossref PubMed Scopus (65) Google Scholar, 11Rao C.N. Reddy P. Liu Y. O'Toole E. Reeder D. Foster D.C. Kisiel W. Woodley D.T. Arch. Biochem. Biophys. 1996; 335: 82-92Crossref PubMed Scopus (88) Google Scholar, 12Iino M. Foster D.C. Kisiel W. Arterioscler. Thromb. Vasc. Biol. 1998; 18: 40-46Crossref PubMed Scopus (93) Google Scholar). hTFPI-2 can prevent the conversion of Pro-MMP-1 (matrix metalloprotease 1, interstitial collagenase) and Pro-MMP-3 (matrix metalloprotease 3, stromelysin-1/transin-1) into MMP-1 and MMP-3 by plasmin and trypsin (13Rao C.N. Mohanam S. Puppala A. Rao J.S. Biochem. Biophys. Res. Commun. 1999; 255: 94-98Crossref PubMed Scopus (87) Google Scholar) and therefore might indirectly regulate matrix proteolysis and connective tissue turnover. The role of hTFPI-2 in cancer progression is not completely elucidated. On one hand, hTFPI-2 has an anti-invasive effect that might be mediated via inhibition of plasmin that activates proteases promoting degradation of the extracellular matrix and tumor invasion. Several tumor cell lines were less invasive when they were stably transfected with hTFPI-2 cDNA (14Jin M. Udagawa K. Miyagi E. Nakazawa T. Hirahara F. Yasumitsu H. Miyazaki K. Nagashima Y. Aoki I. Miyagi Y. Gynecol. Oncol. 2001; 83: 325-333Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 15Konduri S.D. Tasiou A. Chandrasekar N. Nicolson G.L. Rao J.S. Clin. Exp. Metastasis. 2000; 18: 303-308Crossref PubMed Scopus (41) Google Scholar, 16Konduri S.D. Rao C.N. Chandrasekar N. Tasiou A. Mohanam S. Kin Y. Lakka S.S. Dinh D. Olivero W.C. Gujrati M. Foster D.C. Kisiel W. Rao J.S. Oncogene. 2001; 20: 6938-6945Crossref PubMed Scopus (72) Google Scholar, 17Konduri S.D. Tasiou A. Chandrasekar N. Rao J.S. Int. J. Oncol. 2001; 18: 127-131PubMed Google Scholar). On the other hand, hTFPI-2 has been to have a effect in carcinoma cells T. A. Foster D.C. A. Kisiel W. J. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). this we the signaling pathway and elements that regulate the of the hTFPI-2 gene in epithelial cells. it has been that PMA can hTFPI-2 gene in cells and that the promoter region to is minimal and inducible promoter activity of hTFPI-2 S.D. Rao C.N. H. N. Tasiou A. Dinh Olivero W.C. Gujrati M. Foster D.C. Kisiel W. Rao J.S. Oncogene. 2002; PubMed Scopus Google the signal transduction pathway by which PMA gene of hTFPI-2 and the promoter elements in hTFPI-2 regulation have not been in we that the hTFPI-2 gene is regulated by the ERK/MAPK signaling pathway and that the activity of this pathway is to an AP-1 site in the promoter of the hTFPI-2 gene. The Phorbol 12-myristate 13-acetate was and human epidermal growth factor The as well as the including EcR-293 cells, and and the were The MEK inhibitor and the were The MAPK was The and the and were The mutagenesis was The was The and MCF7 cell lines were the cell lines were in Dulbecco's modified Eagle's medium with the A549 cell which was in with The the gene with a to at position and a a between a and a positions one and was a The was with the and the in with The was by and cloned into the site of A. K. J. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) as a to the domain of the and in the an site in was to the of the into of A in was by the and into the site of an site in The nucleotide was by The was and cloned in the of in a was A. K. J. J. Biol. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar) by and cloned into the of was by mutagenesis mutagenesis The that were to a serine to in are in in I. The nucleotide was by and the was and cloned into the of The was by H. of The was with the was in with and was and cloned into the of was cells. The cells were in in a and and with proteinase at and the was and in A of the 5′-flanking region of the hTFPI-2 was with an the and to a and a site in was cloned into the which the luciferase reporter Google Scholar) and was a The construct was The was found to the one by S. Y. Foster D.C. Kisiel W. Biophys. 2001; PubMed Scopus Google Scholar) a C to A at nucleotide position to the The reporter and were by the The was with and and the were by The by and was in with and the were cloned into the site of The Sp1 transcription factor binding site between nucleotide positions and was to the AP-1 between nucleotide positions and −156 was to and the and between nucleotide positions and was modified to the nucleotide were and cloned into the of was by The used were and and and and and were by the the and constructs the AP-1 site between nucleotide positions and −156 was and the Sp1 site between nucleotide positions and −134 to the site between nucleotide positions and was to The and are in and the nucleotide are The were by and into the of inhibitor the HEK293 cells were the to The cells were with of and of a T. 1997; PubMed Scopus Google Scholar). the cells were the inhibitor was to PMA The cells were in phosphate-buffered saline and into in one were cell and at and the cell was luciferase activity the luciferase reporter was by a The cells in the second were and and the of cells that was by to of protein by the was activity was expressed as of protein and and MCF7 cells were into at and to cells were transfected with of the reporter gene HEK293 and HeLa cells were transfected with at a of of and A549 and MCF7 cells were transfected with to the the cells of well were into of a the cells were and with PMA as Cell were and as described The of luciferase was as of protein of cells by the of protein of cells. to EcR-293 cells in with and were into at EcR-293 cells stably the modified A gene of cloned into a inducible can be induced with the A that binds to the were transfected with of and of of of reporter and of The medium was with A was to the medium to protein at a of and cells were activity was expressed as of protein and were and with The cells were in and the proteinase and of protein was by and to The were blocked with in and with the at a of at with at of at The MAPK was in and with the to the were by We have that the hTFPI-2 gene was highly up-regulated that were with HEK293 cells with PMA not PMA induction of a reporter gene has been in cells S.D. Rao C.N. H. N. Tasiou A. Dinh Olivero W.C. Gujrati M. Foster D.C. Kisiel W. Rao J.S. Oncogene. 2002; PubMed Scopus Google and of hTFPI-2 is up-regulated in and cells with PMA S. P. F. P. Y. Thromb. Res. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). To study the signaling pathway that leads to the induction of hTFPI-2 gene by PMA and to promoter elements in we a of the 5′-flanking region of the hTFPI-2 gene HEK293 cells and cloned the adjacent to the luciferase reporter gene To this potential promoter region transcription of we transfected HEK293 cells with the reporter and in luciferase activity of and cells. with PMA a of luciferase with cells PMA of the luciferase reporter gene was by cells were with the inhibitor at a of completely PMA induction at a of suggesting that PMA activates the hTFPI-2 promoter through the MEK signaling pathway in the in PMA activated MAPK in HEK293 cells and the phosphorylation of be by the in a This that MEK activation is the induction hTFPI-2 promoter activity by HEK293 cells have been as epithelial cells and may cells S. M. J. 2002; PubMed Scopus Google Scholar). To the PMA induction of the hTFPI-2 gene in HEK293 cells was to this cell PMA of the hTFPI-2 gene in other epithelial cells lines as we transfected human lung carcinoma A549 cells, breast carcinoma MCF7 cells and cervical carcinoma HeLa cells with the luciferase reporter A induction of the hTFPI-2 promoter activity was in A549 cells, whereas PMA induced the hTFPI-2 promoter activity in MCF7 and HeLa cells PMA has been to the epidermal growth factor N. E. Liu J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google we the hTFPI-2 gene be induced by the growth factor up-regulated the hTFPI-2 promoter activity in HeLa cells of the luciferase reporter gene was in A549 and MCF7 cells To the of the components of the ERK/MAPK signaling pathway in the regulation the hTFPI-2 promoter we EcR-293 cells with the and constitutively activated signaling such as the The of luciferase was as luciferase activity in cells active signaling components by the luciferase activity of cells of and in transfected EcR-293 cells is in the constitutively activated signaling components were well of the luciferase reporter gene with the of constitutively active signaling MAPK components of Ras, such as and induced the luciferase reporter the gene indicating that the hTFPI-2 gene can be regulated by the Ras/Raf/MEK/ERK pathway in EcR-293 cells. The activation of the hTFPI-2 promoter was by at positions S. K. 1994; PubMed Scopus Google whereas the and protein M.J. E. Cobb M.H. Curr. Biol. 1998; Full Text Full Text PDF PubMed Google Scholar) activated the hTFPI-2 promoter to a that the Ras/Raf/MEK/ERK signaling pathway regulation of the hTFPI-2 gene. We EcR-293 cells with a series of luciferase reporter gene constructs progressive deletions of the 5′-flanking region with a the The of the are in A. to of luciferase were with constructs through whereas inducible luciferase activity was with construct suggesting that the minimal inducible promoter activity is located between nucleotide positions and −89 were in HEK293 cells the PMA through to whereas was not induced by PMA we to the promoter elements in the region that are the and PMA as with cells. The minimal basal promoter activity includes the basal luciferase activity as whereas basal activity was with construct in the luciferase activity by in cells with cells indicating that the to transcription factor binding basal luciferase were in cells transfected with and a reporter gene construct of an promoter with cells transfected with and a reporter construct a promoter This of activity is to the of basal activity in the region and therefore may be to the of transcription factor binding basal However, we can not that the may elements that can to the inducible activity of the constructs described in of in a To potential cis-acting elements the PMA and of the promoter we used the computer program TFSEARCH that highly the transcription factor binding site by E. R. P. and H. Several transcription factor binding were including a potential Sp1 site between nucleotide positions and a potential AP-1 site between positions and and an Sp1 and between positions and To the of we the Sp1 site at position to in the AP-1 site at positions to to the Sp1 and at positions to and at positions to in The reporter gene and the the −156 AP-1 the in of the site in a 5′-flanking promoter region in a in the basal and inducible activity as with The reporter construct was induced by as with the The of basal activity might be to the of the site the of the to of the AP-1 site a in inducible whereas basal activity was indicating that this AP-1 site is inducible Furthermore, of the site basal and inducible activity of the −156 AP-1 and the site a in inducible activity as with a construct that the −156 AP-1 site suggesting that the site may have a effect inducible promoter basal was to of the −156 AP-1 and the Sp1 in the 5′-flanking region of the hTFPI-2 promoter basal activity and was not by suggesting that elements basal and inducible activity were with MAPK signaling pathway with PMA not that the AP-1 site at position −156 to a cis-acting that is induction of the hTFPI-2 promoter activity by the MEK signaling pathway and the Sp1 site at position −134 to is basal promoter A of the in this study is in We that the hTFPI-2 gene is up-regulated in several epithelial cells by PMA a growth was to promoter activity of the hTFPI-2 gene as in HeLa cells HEK293 cells, induction of the promoter activity by PMA be blocked by the inhibitor suggesting that PMA induction of hTFPI-2 is mediated through a pathway that MEK. activated Ras, and were to gene transcription indicating that the Ras/Raf/MEK/ERK signaling pathway is promoter The ERK/MAPK pathway activates which with and as the AP-1 complex to a P. M. Biophys. PubMed Scopus Google Scholar). We located an AP-1 site at position −156 to as a cis-acting inducible promoter a Sp1 site at positions −134 to of the hTFPI-2 promoter was basal promoter activity study in HEK293 cells that the hTFPI-2 gene is regulated by the Ras/Raf/MEK/ERK signaling pathway. constitutively active signaling of this pathway was to high activity of the hTFPI-2 gene. with reporter gene we of the hTFPI-2 gene in EcR-293 cells to cells not is a activator of the it a to at position and therefore in the active T. M.H. D. 1996; PubMed Scopus Google Scholar). the of that the amino-terminal is a activator of the pathway Curr. Opin. Cell Biol. 1997; 9: PubMed Scopus Google Scholar). with we a induction of hTFPI-2 promoter activity by and a induction by the activator a a D. S.G. K. M. 1994; PubMed Scopus Google Scholar) induction of hTFPI-2 promoter activity not The agent PMA often as a agent to study the by which growth factors regulate growth and differentiation of the cells. PMA the of the activator of protein kinase C S. Curr. Opin. Cell Biol. 1996; PubMed Scopus Google Scholar, W. J. 2000; PubMed Scopus Google and activates by phosphorylation W. R. H. H. D. Nature. PubMed Scopus Google Scholar). However, activation of by is in several cell lines R. Y. H. C.J. 1998; PubMed Scopus Google Scholar, A. R. A. C.J. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). the phorbol can be by the and may be to phorbol such as the and to a phorbol that a role in PMA activation of D. J. 1999; PubMed Scopus Google Scholar). Furthermore, PMA has been to the epidermal growth factor in epidermal cells, and PMA-induced tumor may be mediated through this N. E. Liu J. Biol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). PMA can of such as the mitogen-responsive ERKs the stress-responsive amino-terminal protein and p38 The pathways induced by PMA are cell PMA activates the pathway in but not in HeLa cells, HEK293 cells H. A. S. R. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, H. D. I. A. P. P. J. 1995; PubMed Scopus Google Scholar). this we that hTFPI-2 gene induced by PMA is regulated through the Ras/Raf/MEK/ERK signaling pathway. The MEK inhibitor PMA indicating that activation is induction of hTFPI-2 promoter activity by PMA promoter activation at the used of we that the ERK/MAPK pathway may be PMA induction of hTFPI-2. the hTFPI-2 promoter a effect basal of the hTFPI-2 gene probably to the of activation of hTFPI-2 by MAPK signaling of the ERK/MAPK induction of genes through phosphorylation of complex factors E. M. Oncogene. 2001; 20: PubMed Scopus Google Scholar). we have of when PMA-induced HEK293 cells were not with to the AP-1 which activates gene transcription by binding to the AP-1 Furthermore, can lead to transcription through binding to the AP-1 in the promoter E. M. Oncogene. 2001; 20: PubMed Scopus Google Scholar). with we located a AP-1 site at position −156 to as inducible promoter that basal promoter activity is located in the to −89 of the hTFPI-2 promoter with a promoter study in human endothelial cells S. Y. Foster D.C. Kisiel W. Biophys. 2001; PubMed Scopus Google an to the to region in that of the basal to we have identified a Sp1 site at −134 to that is the basal activity in the promoter to −89 The to −89 is a and an PMA induction of the hTFPI-2 promoter activity as with basal We therefore the transcription factor binding in this promoter region and found that the AP-1 site at position −156 to is induction of promoter activity by S.D. Rao C.N. H. N. Tasiou A. Dinh Olivero W.C. Gujrati M. Foster D.C. Kisiel W. Rao J.S. Oncogene. 2002; PubMed Scopus Google Scholar) identified a region between and in the hTFPI-2 promoter region that is to hTFPI-2 promoter regulation in cells, found a in the region between to and elements between and These and elements found in cells might be we not such elements in HEK293 cells. luciferase were in constructs of between and induced by PMA not suggested that three potential AP-1 to to to and to −156 in may be in gene induction S.D. Rao C.N. H. N. Tasiou A. Dinh Olivero W.C. Gujrati M. Foster D.C. Kisiel W. Rao J.S. Oncogene. 2002; PubMed Scopus Google Scholar). we identified the −156 to AP-1 site as transcription of the hTFPI-2 gene, that the to promoter may not be gene induction in EcR-293 cells, the promoter of construct which the is a induction to constructs The ERK/MAPK pathway by growth factors and phorbol is associated with proliferation and The of hTFPI-2 induction by the ERK/MAPK pathway and the role of hTFPI-2 in tumor progression is not On one hand, several cell lines stably hTFPI-2, such as cells, cells, cells, and cancer cells, were less invasive cells (14Jin M. Udagawa K. Miyagi E. Nakazawa T. Hirahara F. Yasumitsu H. Miyazaki K. Nagashima Y. Aoki I. Miyagi Y. Gynecol. Oncol. 2001; 83: 325-333Abstract Full Text PDF PubMed Scopus (43) Google Scholar, 15Konduri S.D. Tasiou A. Chandrasekar N. Nicolson G.L. Rao J.S. Clin. Exp. Metastasis. 2000; 18: 303-308Crossref PubMed Scopus (41) Google Scholar, 16Konduri S.D. Rao C.N. Chandrasekar N. Tasiou A. Mohanam S. Kin Y. Lakka S.S. Dinh D. Olivero W.C. Gujrati M. Foster D.C. Kisiel W. Rao J.S. Oncogene. 2001; 20: 6938-6945Crossref PubMed Scopus (72) Google Scholar, 17Konduri S.D. Tasiou A. Chandrasekar N. Rao J.S. Int. J. Oncol. 2001; 18: 127-131PubMed Google Scholar) and of hTFPI-2 the of cells as in a C.N. Lakka S.S. Kin Y. S.D. Mohanam S. Rao J.S. Clin. Cancer Res. 2001; Google Scholar). On the other hand, hTFPI-2 has been to have a effect in hTFPI-2 has been to be a E. Y. R. M. R. T. Y. Y. K. Y. S. J. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google and hTFPI-2 growth invasion of human carcinoma cells and is of invasion of human carcinoma T. A. Foster D.C. A. Kisiel W. J. J. Biol. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). has been described tissue of of tissue of inhibit the activity of matrix by binding to binding but they are in the cell activation and are J. J. 1999; PubMed Scopus Google Scholar). the may a variety of and regulation of may play an role in the of protease in the We M. Cobb the of the N. the and M. the luciferase We M. M. and U. the

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.