PubMed:15585645 JSONTXT

{"target":"https://pubannotation.org/docs/sourcedb/PubMed/sourceid/15585645","sourcedb":"PubMed","sourceid":"15585645","source_url":"http://www.ncbi.nlm.nih.gov/pubmed/15585645","text":"Histone deacetylase inhibitor trichostatin A represses estrogen receptor alpha-dependent transcription and promotes proteasomal degradation of cyclin D1 in human breast carcinoma cell lines.\nPURPOSE: Estrogen receptor alpha (ERalpha)-positive breast cancer cell lines are up to 10 times more sensitive than ERalpha-negative cell lines to the antiproliferative activity of the histone deacetylase inhibitor trichostatin A (TSA). The purpose of the study was to investigate the mechanisms underlying this differential response.\nEXPERIMENTAL DESIGN AND RESULTS: In the ERalpha-positive MCF-7 cell line, TSA repressed ERalpha and cyclin D1 transcription and induced ubiquitin dependent proteasomal degradation of cyclin D1, leading primarily to G(1)-S-phase cell cycle arrest. By contrast, cyclin D1 degradation was enhanced but its transcription unaffected by TSA in the ERalpha-negative MDA-MB-231 cell line, which arrested in G(2)-M phase. Cyclin D1 degradation involved Skp2/p45, a regulatory component of the Skp1/Cullin/F-box complex; silencing SKP2 gene expression by RNA interference stabilized cyclin D1 and abrogated the cyclin D1 down-regulation response to TSA.\nCONCLUSIONS: Tamoxifen has been shown to inhibit ERalpha-mediated cyclin D1 transcription, and acquired resistance to tamoxifen is associated with a shift to ERalpha-independent cyclin D1 up-regulation. Taken together, our data show that TSA effectively induces cyclin D1 down-regulation through both ERalpha-dependent and ERalpha-independent mechanisms, providing an important new strategy for combating resistance to antiestrogens.","tracks":[{"project":"DisGeNET","denotations":[{"id":"T0","span":{"begin":143,"end":152},"obj":"gene:595"},{"id":"T1","span":{"begin":162,"end":178},"obj":"disease:C0006142"},{"id":"T2","span":{"begin":143,"end":152},"obj":"gene:595"},{"id":"T3","span":{"begin":162,"end":178},"obj":"disease:C0678222"}],"relations":[{"id":"R1","pred":"associated_with","subj":"T0","obj":"T1"},{"id":"R2","pred":"associated_with","subj":"T2","obj":"T3"}],"namespaces":[{"prefix":"gene","uri":"http://www.ncbi.nlm.nih.gov/gene/"},{"prefix":"disease","uri":"http://purl.bioontology.org/ontology/MEDLINEPLUS/"}],"attributes":[{"subj":"T0","pred":"source","obj":"DisGeNET"},{"subj":"T1","pred":"source","obj":"DisGeNET"},{"subj":"T2","pred":"source","obj":"DisGeNET"},{"subj":"T3","pred":"source","obj":"DisGeNET"}]},{"project":"DisGeNET5_gene_disease","denotations":[{"id":"15585645-0#55#72#gene2099","span":{"begin":55,"end":72},"obj":"gene2099"},{"id":"15585645-0#143#152#gene595","span":{"begin":143,"end":152},"obj":"gene595"},{"id":"15585645-0#162#178#diseaseC0678222","span":{"begin":162,"end":178},"obj":"diseaseC0678222"},{"id":"15585645-1#0#17#gene2099","span":{"begin":200,"end":217},"obj":"gene2099"},{"id":"15585645-1#43#56#diseaseC0006142","span":{"begin":243,"end":256},"obj":"diseaseC0006142"}],"relations":[{"id":"55#72#gene2099162#178#diseaseC0678222","pred":"associated_with","subj":"15585645-0#55#72#gene2099","obj":"15585645-0#162#178#diseaseC0678222"},{"id":"143#152#gene595162#178#diseaseC0678222","pred":"associated_with","subj":"15585645-0#143#152#gene595","obj":"15585645-0#162#178#diseaseC0678222"},{"id":"0#17#gene209943#56#diseaseC0006142","pred":"associated_with","subj":"15585645-1#0#17#gene2099","obj":"15585645-1#43#56#diseaseC0006142"}],"attributes":[{"subj":"15585645-0#55#72#gene2099","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"15585645-0#143#152#gene595","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"15585645-0#162#178#diseaseC0678222","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"15585645-1#0#17#gene2099","pred":"source","obj":"DisGeNET5_gene_disease"},{"subj":"15585645-1#43#56#diseaseC0006142","pred":"source","obj":"DisGeNET5_gene_disease"}]},{"project":"PubMed_Structured_Abstracts","denotations":[{"id":"T1","span":{"begin":200,"end":525},"obj":"OBJECTIVE"},{"id":"T2","span":{"begin":559,"end":1169},"obj":"RESULTS"},{"id":"T3","span":{"begin":1183,"end":1603},"obj":"CONCLUSIONS"}],"attributes":[{"subj":"T1","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T2","pred":"source","obj":"PubMed_Structured_Abstracts"},{"subj":"T3","pred":"source","obj":"PubMed_Structured_Abstracts"}]}],"config":{"attribute types":[{"pred":"source","value type":"selection","values":[{"id":"DisGeNET","color":"#aa93ec","default":true},{"id":"DisGeNET5_gene_disease","color":"#96ec93"},{"id":"PubMed_Structured_Abstracts","color":"#ec93b0"}]}]}}