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Negative Regulation of Transcription Coactivator p300 by Orphan Receptor TR3

Author: LiGuiDeng
Tutor: WuQiao
School: Xiamen University
Course: Cell Biology
Keywords: Orphan receptor TR3 p300 HAT activity
CLC: Q343
Type: Master's thesis
Year: 2008
Downloads: 44
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Abstract

p300 can be activated by forming a complex or by promoting histone acetylation to regulate the transcriptional activity of a series of transcription factors. Play an important role in the process of adjusting a plurality of signal paths at the transcriptional level. External physiological stimuli conditions, p300 regulate gene expression, which led to a series of changes in physiological functions such as cell proliferation, differentiation and apoptosis. The nuclear orphan receptor TR3 belongs to the steroid / thyroid receptor superfamily members. TR3 is a legislation as early genes, can be serum, phorbol ester and growth factor-induced expression. Played an important role in the TR3 in apoptosis, proliferation, differentiation and development process. Our laboratory has confirmed TR3 able to combine with p53, inhibiting p53 acetylation and transcriptional activity, reduced mRNA levels of MDM2. We also found that the and TR3 of can be used as a negative regulatory factor, retinoic acid receptor RXRα to inhibit binding by competition with p300 RXRα acetylated, so that the p300 induced RXRα transcriptional activity is inhibited. These early results are caused by our way of thinking, that TR3 whether dependent regulation of p300 acetylation specificity negative regulation of other transcription factors.? TR3 will affect p300 histone deacetylase activity it? For this reason, we TR3 regulation of p300-mediated acetylation mechanism to carry out in-depth research. We found that, TR3 can be a negative regulator of the activity of the transcriptional co-activator p300. Co-immunoprecipitation experiments show, TR3 and p300 interaction, and inhibition of a series of transcription factors induced by p300 acetylation levels and transcriptional activity. Further studies showed that, the the p300 molecule on the conserved sequence the TRAM (Transcriptional adaptermotif) and TR3 molecules the special FLELFIL amino acid sequences of both interaction sequence. TR3 through and p300, completely covering the area of ??the p300 histone deacetylase activity, thereby inhibiting histone deacetylase activity (HAT). When TRAM area are cut, TR3 can still bind to the CH2 region of p300 HAT activity, but it can not suppress. Therefore, TRAM TR3 inhibition of HAT activity necessary binding sites. When the full-length TR3 or TR3 deletion mutant FLELFIL sequence, F and E A, TR3 inhibition of p300 HAT activity will lose. These results not only illustrate TR3 inhibition of p300 HAT activity may be dependent on FLELFIL and TRAM sequences combined with each other and identifying also the confirmed sequence FLELFIL TR3 regulation of transcription of the transcription factor activation activity crucial. In addition, we extracted from the fungus a TR3 agonist, it can inhibit p300 HAT activity. More importantly, TR3 specific targets, can be used as the agonist because siRNA silencing endogenous TR3, agonists of p300 HAT activity and transcriptional activation of the transcription factor can not be suppressed. The TR3 agonist treatment of breast cancer cells, AR and p300-mediated proliferation of breast cancer cells was significantly inhibited. Therefore, our study not only confirmed TR3 through inhibition of p300 HAT activity to inhibit the proliferation of breast cancer cells, but also prompted the TR3 agonist may lead compounds can be used as an anticancer drug. In summary, the results of our study not only found TR3 as a transcriptional repressor new features, and also to elucidate the molecular mechanisms of its the p300 histone deacetylase activity regulation.

Negative Regulation of Transcription Coactivator p300 by Orphan Receptor TR3

Abstract

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