PubMed:10051488 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/10051488","sourcedb":"PubMed","sourceid":"10051488","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/10051488","text":"Control of the tissue inhibitor of metalloproteinases-1 promoter in culture-activated rat hepatic stellate cells: regulation by activator protein-1 DNA binding proteins.\nIn the injured liver hepatic stellate cells (HSCs) undergo a dramatic phenotypic transformation known as \"activation\" in which they become myofibroblast-like and express high levels of the tissue inhibitor of metalloproteinase 1 (TIMP-1). HSC activation is accompanied by transactivation of the TIMP-1 promoter. Truncation mutagenesis studies delineated a minimal active promoter consisting of nucleotides -102 to +60 relative to the major start site for transcription. Removal of an AP-1 site located at nucleotides -93 to -87 caused almost a complete loss of promoter activity. Analysis of AP-1 DNA binding activities during culture activation of HSCs initially indicated transient expression of proteins capable of forming a low mobility AP-1 DNA binding complex (LMAP-1). LMAP-1 was maximally induced at 24 hours of culture and then fell to undetectable levels at 120 hours. Western blot studies showed that both c-Fos and c-Jun underwent similar transient inductions. These temporal changes in c-Fos and c-Jun activities were unexpected because TIMP-1 mRNA expression is not detected in HSCs until culture day 3 to 5 and is thereafter sustained at a high level. Previous work in other cell lineages has established a key role for Pea3 binding proteins (Ets-1) in AP-1 mediated transactivation of the TIMP-1 promoter. We show that HSCs express relatively low levels Ets-1 and Ets-2 and show that mutagenesis of the Pea3 DNA binding site in the TIMP-1 promoter has less than a twofold effect on its activity in activated HSCs. Further analysis of AP-1 DNA binding activities in 7- to 14-day culture activated HSCs led to the discovery of high mobility AP-1 complexes (HMAP-1). HMAP-1 DNA binding activities were sequence specific with respect to AP-1 and absent from freshly isolated HSCs. Supershift EMSA and Western blot studies identified JunD, Fra2, and FosB as potential components of the HMAP-1. Mutations of the AP-1 site of the TIMP-1 promoter that prevented formation of HMAP-1 caused a 70% loss of activity in transfected activated HSCs. Taken together the data indicate that sustained upregulation of TIMP-1 gene expression may be at least partially controlled by a novel AP-1 dependent regulation of TIMP-1 promoter activity.","tracks":[{"project":"FSU-PRGE","denotations":[{"id":"T1","span":{"begin":15,"end":55},"obj":"protein"},{"id":"T2","span":{"begin":128,"end":147},"obj":"protein"},{"id":"T3","span":{"begin":359,"end":398},"obj":"protein"},{"id":"T4","span":{"begin":400,"end":406},"obj":"protein"},{"id":"T5","span":{"begin":465,"end":471},"obj":"protein"},{"id":"T6","span":{"begin":654,"end":658},"obj":"protein"},{"id":"T7","span":{"begin":762,"end":766},"obj":"protein"},{"id":"T8","span":{"begin":911,"end":915},"obj":"protein"},{"id":"T9","span":{"begin":937,"end":943},"obj":"protein"},{"id":"T10","span":{"begin":946,"end":952},"obj":"protein"},{"id":"T11","span":{"begin":1087,"end":1092},"obj":"protein"},{"id":"T12","span":{"begin":1097,"end":1102},"obj":"protein"},{"id":"T13","span":{"begin":1169,"end":1174},"obj":"protein"},{"id":"T14","span":{"begin":1179,"end":1184},"obj":"protein"},{"id":"T15","span":{"begin":1220,"end":1226},"obj":"protein"},{"id":"T16","span":{"begin":1405,"end":1409},"obj":"protein"},{"id":"T17","span":{"begin":1428,"end":1433},"obj":"protein"},{"id":"T18","span":{"begin":1438,"end":1442},"obj":"protein"},{"id":"T19","span":{"begin":1475,"end":1481},"obj":"protein"},{"id":"T20","span":{"begin":1540,"end":1545},"obj":"protein"},{"id":"T21","span":{"begin":1550,"end":1555},"obj":"protein"},{"id":"T22","span":{"begin":1589,"end":1593},"obj":"protein"},{"id":"T23","span":{"begin":1618,"end":1624},"obj":"protein"},{"id":"T24","span":{"begin":1720,"end":1724},"obj":"protein"},{"id":"T25","span":{"begin":1825,"end":1829},"obj":"protein"},{"id":"T26","span":{"begin":1841,"end":1847},"obj":"protein"},{"id":"T27","span":{"begin":1850,"end":1856},"obj":"protein"},{"id":"T28","span":{"begin":1919,"end":1923},"obj":"protein"},{"id":"T29","span":{"begin":2015,"end":2019},"obj":"protein"},{"id":"T30","span":{"begin":2021,"end":2025},"obj":"protein"},{"id":"T31","span":{"begin":2031,"end":2035},"obj":"protein"},{"id":"T32","span":{"begin":2067,"end":2073},"obj":"protein"},{"id":"T33","span":{"begin":2092,"end":2096},"obj":"protein"},{"id":"T34","span":{"begin":2109,"end":2115},"obj":"protein"},{"id":"T35","span":{"begin":2153,"end":2159},"obj":"protein"},{"id":"T36","span":{"begin":2285,"end":2291},"obj":"protein"},{"id":"T37","span":{"begin":2356,"end":2360},"obj":"protein"},{"id":"T38","span":{"begin":2385,"end":2391},"obj":"protein"}],"attributes":[{"subj":"T1","pred":"source","obj":"FSU-PRGE"},{"subj":"T2","pred":"source","obj":"FSU-PRGE"},{"subj":"T3","pred":"source","obj":"FSU-PRGE"},{"subj":"T4","pred":"source","obj":"FSU-PRGE"},{"subj":"T5","pred":"source","obj":"FSU-PRGE"},{"subj":"T6","pred":"source","obj":"FSU-PRGE"},{"subj":"T7","pred":"source","obj":"FSU-PRGE"},{"subj":"T8","pred":"source","obj":"FSU-PRGE"},{"subj":"T9","pred":"source","obj":"FSU-PRGE"},{"subj":"T10","pred":"source","obj":"FSU-PRGE"},{"subj":"T11","pred":"source","obj":"FSU-PRGE"},{"subj":"T12","pred":"source","obj":"FSU-PRGE"},{"subj":"T13","pred":"source","obj":"FSU-PRGE"},{"subj":"T14","pred":"source","obj":"FSU-PRGE"},{"subj":"T15","pred":"source","obj":"FSU-PRGE"},{"subj":"T16","pred":"source","obj":"FSU-PRGE"},{"subj":"T17","pred":"source","obj":"FSU-PRGE"},{"subj":"T18","pred":"source","obj":"FSU-PRGE"},{"subj":"T19","pred":"source","obj":"FSU-PRGE"},{"subj":"T20","pred":"source","obj":"FSU-PRGE"},{"subj":"T21","pred":"source","obj":"FSU-PRGE"},{"subj":"T22","pred":"source","obj":"FSU-PRGE"},{"subj":"T23","pred":"source","obj":"FSU-PRGE"},{"subj":"T24","pred":"source","obj":"FSU-PRGE"},{"subj":"T25","pred":"source","obj":"FSU-PRGE"},{"subj":"T26","pred":"source","obj":"FSU-PRGE"},{"subj":"T27","pred":"source","obj":"FSU-PRGE"},{"subj":"T28","pred":"source","obj":"FSU-PRGE"},{"subj":"T29","pred":"source","obj":"FSU-PRGE"},{"subj":"T30","pred":"source","obj":"FSU-PRGE"},{"subj":"T31","pred":"source","obj":"FSU-PRGE"},{"subj":"T32","pred":"source","obj":"FSU-PRGE"},{"subj":"T33","pred":"source","obj":"FSU-PRGE"},{"subj":"T34","pred":"source","obj":"FSU-PRGE"},{"subj":"T35","pred":"source","obj":"FSU-PRGE"},{"subj":"T36","pred":"source","obj":"FSU-PRGE"},{"subj":"T37","pred":"source","obj":"FSU-PRGE"},{"subj":"T38","pred":"source","obj":"FSU-PRGE"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"FSU-PRGE","color":"#ec93cf","default":true}]}]}}