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dc.contributor.authorRoca, Ren_US
dc.contributor.authorKypta, RMen_US
dc.contributor.authorVivanco, MDen_US
dc.date.accessioned2018-09-17T08:23:32Z
dc.date.issued2003-03-18en_US
dc.identifier6en_US
dc.identifier.citationPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 pp. 3113 - 3118en_US
dc.identifier.issn0027-8424en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2691
dc.identifier.doi10.1073/pnas.0634912100en_US
dc.description.abstract‘Glucocorticoids inhibit proliferation of many cell types, but the relationship between the glucocorticoid receptor (GR) and the proteins regulating cell cycle progression is not fully understood. We previously found that during fibrosarcoma (FS) progression, GR displays only modest transcriptional activity in the preneoplastic stages, whereas it is highly active in FS cells. Now, we report that glucocorticoids reduce proliferation throughout FS development. The cyclin-dependent kinase inhibitor p16(INK4a) is frequently absent in many cancers, including FSs. We observed that p16(INK4a) protein expression is lost at the tumor stage of FS progression. Treatment with the demethylating agent 5-aza-2’-deoxycytidine restores p16(INK4a) expression and reverts the phenotype of FS cells to low GR transcriptional activity, similar to that of the p16(INKa)-expressing preneoplastic stages. Importantly,exogenous p16(INK4a) introduced by cotransfection is sufficient to reduce GR activity in FS cells, without affecting GR activity in p16-positive aggressive fibromatosis cells. Furthermore, GR transcriptional activity is elevated in mouse embryo fibroblasts derived from INK4a(-/-) mice compared with those derived from WT mice, implying that the difference in p16(INK4a) expression is sufficient to modulate GR activity. These results suggest a relationship between steroid hormone receptor activity and cell cycle inhibition, whereby absence of p16(INK4a) protein leads to higher GR transactivation activity and reduced cell sensitivity to dexamethasone. This observation might have important implications for current cancer therapies.en_US
dc.format.extent3113 - 3118en_US
dc.languageEnglishen_US
dc.language.isoEnglishen_US
dc.publisherNATL ACAD SCIENCESen_US
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.titleLoss of P16(INK4a) results in increased glucocorticoid receptor activity during fibrosarcoma developmenten_US
dc.typeJournal Article
rioxxterms.versionofrecord10.1073/pnas.0634912100en_US
rioxxterms.licenseref.startdate2003-03-18en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAen_US
pubs.notesaffiliation: Vivanco, MD (Reprint Author), Univ London Imperial Coll Sci Technol & Med, Prostate Canc Res Grp, Dept Canc Med, Div Med, Du Cane Rd, London W12 0NN, England. Univ London Imperial Coll Sci Technol & Med, Prostate Canc Res Grp, Dept Canc Med, Div Med, London W12 0NN, England. Inst Canc Res, Breakthrough Toby Robins Breast Canc Res Ctr, London SW3 6JB, England. keywords-plus: CELL-CYCLE ARREST; RAT MAMMARY-TUMOR; TRANSGENIC MICE; TRANSCRIPTIONAL ACTIVATION; INDUCED APOPTOSIS; RETINOBLASTOMA-PROTEIN; HOMOZYGOUS DELETION; GENETIC PROGRESSION; HUMAN CANCERS; METHYLATION research-areas: Science & Technology - Other Topics web-of-science-categories: Multidisciplinary Sciences author-email: mariav@icr.ac.uk researcherid-numbers: Kypta, Robert/F-7699-2011 Kypta, Robert/G-2407-2011 Vivanco, Maria/G-2393-2011 orcid-numbers: Kypta, Robert/0000-0002-2389-310X Vivanco, Maria/0000-0002-9540-247X number-of-cited-references: 53 times-cited: 7 usage-count-last-180-days: 0 usage-count-since-2013: 2 journal-iso: Proc. Natl. Acad. Sci. U. S. A. doc-delivery-number: 657PH unique-id: ISI:000181675200027 oa: gold_or_bronze da: 2018-09-13en_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.volume100en_US
pubs.embargo.termsNot knownen_US
dc.contributor.icrauthorVivanco, Mariaen_US


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