Role of TAF12 in the Increased VDR Activity in Paget's Disease of Bone
Abstract
Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25- dihydroxyvitamin D3 (1,25-(OH)2D3; also known as calcitriol). The increased 1,25- (OH)2D3 sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of vitamin D receptor (VDR) mediated transcriptionTAF12 is present at much higher levels in MVNP-expressing OCL precursors than normals. These results suggest that TAF12 plays an important role in the abnormal OCL activity in PD. However, the molecular mechanisms underlying both 1,25-(OH)2D3's effects on OCL formation and the contribution of TAF12 to these effects in both normals and PD patients are unclear. Inhibition of TAF12 with a specific TAF12 anti-sense construct decreased OCL formation and the sensitivity of OCL precursors to 1,25-(OH)2D3 in PD patient bone marrow samples. Further, OCL precursors from transgenic mice in which TAF12 expression was targeted to the OCL lineage (tartrate-resistant acid phosphatase TRAP-TAF12 mice), formed OCLs at very low levels of 1,25-(OH)2D3, although the OCLs failed to exhibit other hallmarks of PD OCLs, including hypermultinucleation and receptor activator of NF- B ligand (RANKL) hypersensitivity. Chromatin immunoprecipitation (ChIP) analysis of OCL precursors using an anti- TAF12 antibody demonstrated that TAF12 binds the 24-hydroxylase (CYP24A1) promoter, which contains two functional vitamin D response elements (VDREs), in the presence of 1,25-(OH)2D3. Because TAF12 directly interacts with the cyclic adenosine monophosphate dependent activating transcription factor 7 (ATF7) and potentiates ATF7-induced transcriptional activation of ATF7-driven genes in other cell types, we determined whether TAF12 is a functional partner of ATF7 in OCL precursors.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2014
- Accession Number
- ADA613487
Entities
People
- Noriyoshi Kurihara
Organizations
- Indiana University