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Transcription Ligand-Dependent Transcription of Retinoid-Target genes


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Transcription Ligand-Dependent Transcription of Retinoid-Target genes

Ligand Dependent Transcription of Retinoid-Target genes

Retinoid receptors are asymmetrically oriented Retinoic acid receptor (RAR)/ RetinoidX receptor (RXR) heterodimers that bind to specific DNA sequences or Retinoic acidresponse elements (RAREs) in the promoters of a large number of retinoid-target genes[1], [2], [3].

Receptors heterodimers bind retinoid ligands. This interaction is facilitated byCellular retinoic acid binding protein 2 ( CRABP2 ) and is stabilized by CyclinD3 [4], [5].

Ligand-bound heterodimers recruit nuclear receptor co-activators, such as Nuclearreceptor coactivators 1, 2 and 3 ( NCOA1 (SRC-1), NCOA2 (GRIP1/TIF2), andNCOA2 (pCIP/SRC3) ), histone methyltransferases and acetyltransferases (CARM1, p300, CBP and PCAF ) [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Thisleads to further chromatin decompaction. Subsequently, retinoid receptors become capableof recruiting the basal transcriptional machinery, including General transcriptionfactors II H, II F, II B, II D, and II A ( TFIIH, TFIIF, TFIIB,TFIID, and TFIIA )) via their association with the mediator complex,Thyroid hormone receptor alpha-associated protein and SRB/MED-containing cofactor complex( TRAP/SMCC complex ). The mediator complex then binds RNA polymerase IIholoenzyme and thus expedites the access of the basal transcriptional machinery to thepromoter [17], [13].

26S proteasome system regulates the magnitude and duration of theretinoid-mediated transcription.

In the absence of the ligand, the DNA-bound heterodimer RAR-alpha/RXR-alpha can repress their targets by recruiting co-repressor supercomplexescontaining Histone deacetylase class I complex, Sin3 complex and co-repressorsNuclear receptor co-repressor 1 and 2 ( N-CoR and SMRT ). Sin3 complexcontains Sin3A-associated protein 18kDa, 30kDa and 130kDa ( SAP18, SAP30and SAP130 )), and SIN3 homolog A ( Sin3a ), as well as several othersubunits [18], [19], [20], [21], [22], [23], [24], [25], [26], [27].