Timeless Is a Novel Estrogen Receptor Co-activator Involved in Multiple Signaling Pathways in MCF-7 Cells.

Autor: Magne Nde CB; Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia. Electronic address: chantal.nde@hudson.org.au., Casas Gimeno G; Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia., Docanto M; Monash University, Clayton, Victoria 3168, Australia., Knower KC; Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia., Young MJ; Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia., Buehn J; Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia., Sayed E; Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia., Clyne CD; Cancer Drugs Discovery, Centre of Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria 3168, Australia; Monash University, Clayton, Victoria 3168, Australia.
Jazyk: angličtina
Zdroj: Journal of molecular biology [J Mol Biol] 2018 May 11; Vol. 430 (10), pp. 1531-1543. Date of Electronic Publication: 2018 Mar 16.
DOI: 10.1016/j.jmb.2018.03.008
Abstrakt: Activation of estrogen receptor α (ERα) stimulates cell division and tumor growth by modulating the expression of ERα target genes. This activation involves the recruitment of specific proteins with activities that are still not fully understood. Timeless, the human homolog of the Drosophila gene involved in circadian rhythm, was previously shown to be a strong predictor of tamoxifen relapse, and is involved in genomic stability and cell cycle control. In this study, we investigated the interplay between Timeless and ERα, and showed that human Timeless is an ERα coactivator. Timeless binds to ERα and enhances its transcriptional activity. Overexpressing Timeless increases PARP1 expression and enhances ERα-induced gene regulation through the proximal LXXLL motif on Timeless protein and ERα PARylation. Finally, Timeless is recruited with ERα on the GREB1 and cMyc promoters. These data, the first to link Timeless to steroid hormone function, provide a mechanistic basis for its clinical association with tamoxifen resistance. Thus, our results identify Timeless as another key regulator of ERα in controlling ERα transactivation.
(Copyright © 2018. Published by Elsevier Ltd.)
Databáze: MEDLINE
Externí odkaz: