PML-RARα induces all-trans retinoic acid-dependent transcriptional activation through interaction with MED1

Transcriptional activation by PML-RARα, an acute promyelocytic leukemia-related oncofusion protein, requires pharmacological concentrations of all-trans retinoic acid (ATRA). However, the mechanism by which the liganded PML-RARα complex leads to the formation of the preinitiation complex has been un...

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Published in:	Transcription Vol. 10; no. 3; pp. 147 - 156
Main Authors:	Fukuoka, Tomoya, Kawai, Asami, Takahara, Taku, Mori, Mahiro, Roeder, Robert G., Hasegawa, Natsumi, Ito, Mitsuhiro
Format:	Journal Article
Language:	English
Published:	United States Taylor & Francis 27-05-2019
Subjects:	Humans LxxLL nuclear receptor recognition motifs MED1 Mediator Mediator Complex Subunit 1 - chemistry Mediator Complex Subunit 1 - metabolism Oncogene Proteins, Fusion - agonists Oncogene Proteins, Fusion - metabolism PML-RARα Protein Binding - drug effects Research Paper transcriptional activation Transcriptional Activation - drug effects Tretinoin - pharmacology MED1 PML–RARα Mediator LxxLL nuclear receptor recognition motifs transcriptional activation
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Summary:	Transcriptional activation by PML-RARα, an acute promyelocytic leukemia-related oncofusion protein, requires pharmacological concentrations of all-trans retinoic acid (ATRA). However, the mechanism by which the liganded PML-RARα complex leads to the formation of the preinitiation complex has been unidentified. Here we demonstrate that the Mediator subunit MED1 plays an important role in the ATRA-dependent activation of the PML-RARα-bound promoter. Luciferase reporter assays showed that PML-RARα induced significant transcription at pharmacological doses (1 μM) of ATRA; however, this was submaximal and equivalent to the level of transcription driven by intact RARα at physiological doses (1 nM) of ATRA. Transcription depended upon the interaction of PML-RARα with the two LxxLL nuclear receptor recognition motifs of MED1, and LxxLL→LxxAA mutations led to minimal transcription. Mechanistically, MED1 interacted ATRA-dependently with the RARα portion of PML-RARα through the two LxxLL motifs of MED1. These results suggest that PML-RARα initiates ATRA-induced transcription through its interaction with MED1.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2154-1264 2154-1272
DOI:	10.1080/21541264.2019.1624467