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论文类型：期刊论文

发表时间：2013-10-10

发表刊物：ONCOGENE

收录刊物：SCIE、PubMed、Scopus

卷号：32

期号：41

页面范围：4883-4891

ISSN号：0950-9232

关键字：CLOCK; ERa; estrogen; sumoylation

摘要：Disruption of the circadian rhythm is now believed to associate with a number of hormone-related cancers, such as breast cancer, in which aberrant estrogen receptor-a (ERa) signaling is a major contributor. However, the molecular mechanisms underlying the function of core clock proteins in cancer are still largely undefined. In this study, we showed that circadian locomotor output cycles kaput (CLOCK), a key circadian protein, can interact with ERa. Furthermore, this interaction was enhanced by estrogen. We also showed that CLOCK can be sumoylated and sumoylation of CLOCK, which is also stimulated by estrogen, had two consequences: (1) it increased the transcriptional activity of CLOCK; and (2) it increased the CLOCK-modulated transcriptional activity of ERa, as shown by increased transcription of cyclin D1. Sumoylation of CLOCK occurred at two lysine residues, K67 and K851. The enhancement of ERa transcriptional activity exerted by wild-type but not mutant (2K/2R) CLOCK in response to estrogen indicated that sumoylation of CLOCK may have an important role in estrogen-dependent signaling. 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) assay conducted with breast cancer cell lines (MCF-7 and T47D) demonstrated that sumoylation of CLOCK stimulated cell growth and increased the proportion of S phase cells in the cell cycle. The results of this study uncovered new insight into the connection between a major circadian protein and a major estrogen-dependent transcription factor, providing the basis for further research into the involvement of circadian proteins in breast cancer.