MCM7 interacts with androgen receptor.
MCM7 is a critical component of the DNA replication licensing complex that controls DNA replication in both yeast and Xenopus. Our previous studies have indicated that MCM7 is both amplified and overexpressed in metastatic prostate cancer. In this study, we found that MCM7 interacts with the androgen receptor (AR) with high affinity both in vitro and in vivo. We identified the AR-binding motif for MCM7, comprised of amino acids 221 to 248, and the MCM7-binding motif for the AR, comprised of amino acids 426 to 475. AR stimulation with high doses of the synthetic androgen R1881 led to a decrease in MCM7 binding to genomic DNA, a reduction of DNA synthesis, decreases in the number of cells progressing through S phase and cell proliferation, whereas low doses produced an increase in the DNA licensing activity of MCM7 and higher levels of cell proliferation. In addition, the MCM7/AR interaction down-regulated MCM7 expression. The gene transcription or repressor activity of AR is dependent on its interaction with MCM7 because either a mutant AR defective in its interaction with MCM7 or a MCM7 knockdown primarily eliminated AR effects on gene expression. Thus, this study reveals a novel mechanism by which AR and MCM7 facilitate each other's function, suggesting that AR-independent activation of MCM7 may be a mechanism by which prostate cancers bypass therapeutically induced AR blockade.
Shi
Yi-Kang
YK
Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15090, USA.
Yu
Yan P
YP
Zhu
Ze-Hua
ZH
Han
Yu-Chen
YC
Ren
Baoguo
B
Nelson
Joel B
JB
Luo
Jian-Hua
JH
D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D015741:Metribolone / Q000378:metabolism; D051379:Mice; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011944:Receptors, Androgen; D011993:Recombinant Fusion Proteins; D015741:Metribolone; C491086:Mcm7 protein, mouse; D064168:Minichromosome Maintenance Complex Component 7