title: Regulation of thrombin-induced plasminogen activator inhibitor-1 in 4T1 murine breast cancer cells.
abstract: Protease-activated receptor-1 (PAR-1) and PAR-2 are overexpressed in cancer cells and activation of these receptors contributes to malignancy. We have recently shown that thrombin activates PAR-1, which induces transactivation of PAR-2, resulting in increased plasminogen activator inhibitor-1 (PAI-1) expression in 4T1 murine mammary adenocarcinoma cells. Our goal was to analyze the signal transduction pathways that regulate thrombin-induced PAI-1 expression. We found that thrombin stimulation activates the ERK1/2-ELK1-EGR1 pathway in 4T1 cells. Furthermore, inhibition of p42/p44 MAPK signaling reduced PAI-1 expression. These results begin to delineate the mechanism by which thrombin activates a PAR-1/PAR-2 complex to induce PAI-1 expression in the 4T1 murine breast cancer cell line.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, North Carolina 27599-7035, USA.
authors.forename: Troy A
authors.initials: TA
authors.lastname: McEachron
authors.forename: Frank C
authors.initials: FC
authors.lastname: Church
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D044463:Receptor, PAR-1 / Q000235:genetics / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D013917:Thrombin / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D017395:Plasminogen Activator Inhibitor 1; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D013917:Thrombin