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Role of Acinus in Regulating Retinoic Acid‐Responsive Gene Pre‐mRNA Splicing
Author(s) -
Wang Fang,
Soprano Kenneth J.,
Soprano Dianne Robert
Publication year - 2015
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.24804
Subject(s) - minigene , acinus , rna splicing , alternative splicing , biology , retinoic acid , exon , microbiology and biotechnology , transactivation , retinoic acid receptor , genetics , biochemistry , gene , transcription factor , rna , pancreas
Acinus‐S’ is a corepressor for retinoic acid receptor (RAR)‐dependent gene transcription and has been suggested to be involved in RNA processing. In this study, the role of Acinus isoforms in regulating pre‐mRNA splicing was explored using in vivo splicing assays. Both Acinus‐L and Acinus‐S’, with the activity of Acinus‐L higher than that of Acinus‐S’, increase the splicing of a retinoic acid (RA)‐responsive minigene containing a weak 5′ splice site but not a RA‐responsive minigene containing a strong 5′ splice site. RA treatment further enhances the splicing of the weak 5′ splice site by Acinus in a dose‐ and time‐dependent manner, suggesting a RA‐dependent activity in addition to a RA‐independent activity of Acinus. The RA‐independent effect of Acinus occurs to varying degrees using minigene constructs containing several different promoters, while the RA‐dependent splicing activity of Acinus is specific for transcripts derived from the minigene driven by a RA response element (RARE)‐containing promoter. This suggests that the ligand‐dependent splicing activity of Acinus is related to the RA‐activated RAR bound to the RARE. The RRM domain is necessary for the RA‐dependent splicing activity of Acinus and the RA‐independent splicing activity of Acinus is repressed by RNPS1. Importantly, measurement of the splicing of endogenous human RARβ and Bcl‐x in vivo demonstrates that Acinus stimulates the use of the weaker alternative 5′ splice site of these two genes in a RA‐dependent manner for RARβ and a RA‐independent manner for Bcl‐x. Taken together, these studies demonstrate that Acinus functions in both RAR‐dependent splicing and RAR‐dependent transcription. J. Cell. Physiol. 230: 791–801, 2015. © 2014 Wiley Periodicals, Inc.