All-trans retinoic acid (RA), as a ligand for retinoic acid receptors (RAR) and retinoid X receptors (RXR), modulates their transcriptional activity. The AF-1 and AF-2 domains mediate the transcriptional activity. The ligand dependent activation of the AF-2 domain by RA is well understood to involve chromosome decompaction in the presence of ligand with the aid of coactivators. The mechanism of the ligand independent action of the AF-1 domain is less clear. The AF-1 domain of RARs may be regulated by interacting proteins such as HACE1. In vitro and in vivo studies in our lab have shown that HACE1 interacts with RARα1, - β1, -β2, -β3, and -γ1 at the variable AF-1 domain. Transactivation studies have shown that HACE1 represses RA dependent transcriptional activity of RARγ1, but not RARβ3 and RARα1. Our original hypothesis proposed that HACE1 represses RAR transcriptional activity by inhibiting RA-dependent degradation of RARs. Current data confirms previous observations that the half life of RARβ3 is shortened in the presence of RA, compared to a vehicle control. Protein stability assays show that HACE1 does not have an effect on degradation of RARβ3 and RARγ1; however, it increases the ligand independent degradation of RARα1.This data suggests the A/B domain of RARγ1 recruits HACE1 for binding which results in transcriptional repression. Also, in a separate mechanism, the A/B domain of RARα1 binds to HACE1 which then accelerates its degradation in a ligand independent manner. The mechanisms behind these novel roles of HACE1 will need to be studied further and may help in understanding the method of AF-1 transcactivation function. / Microbiology and Immunology
| Identifer | oai:union.ndltd.org:TEMPLE/oai:scholarshare.temple.edu:20.500.12613/2123 |
| Date | January 2011 |
| Creators | Payne, Erin J. |
| Contributors | Soprano, Kenneth J., Tsygankov, Alexander Y., Henderson, Earl E. |
| Publisher | Temple University. Libraries |
| Source Sets | Temple University |
| Language | English |
| Detected Language | English |
| Type | Thesis/Dissertation, Text |
| Format | 82 pages |
| Rights | IN COPYRIGHT- This Rights Statement can be used for an Item that is in copyright. Using this statement implies that the organization making this Item available has determined that the Item is in copyright and either is the rights-holder, has obtained permission from the rights-holder(s) to make their Work(s) available, or makes the Item available under an exception or limitation to copyright (including Fair Use) that entitles it to make the Item available., http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | http://dx.doi.org/10.34944/dspace/2105, Theses and Dissertations |
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