title: Role of ATF7-TAF12 interactions in the vitamin D response hypersensitivity of osteoclast precursors in Paget's disease.
abstract: Osteoclast (OCL) precursors from many Paget's disease (PD) patients express measles virus nucleocapsid protein (MVNP) and are hypersensitive to 1,25-dihydroxyvitamin D₂ (1,25-(OH)₂D₃; also know as calcitriol). The increased 1,25-(OH)₂D₃ sensitivity is mediated by transcription initiation factor TFIID subunit 12 (TAF12), a coactivator of the vitamin D receptor (VDR), which 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 antisense construct decreased OCL formation and OCL precursors' sensitivity 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 receptor activator of NF-κB ligand (RANKL) hypersensitivity and hypermultinucleation. 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. Immunoprecipitation of lysates from either wild-type (WT) or MVNP-expressing OCL with an anti-TAF12 antibody, followed by blotting with an anti-ATF7 antibody, or vice versa, showed that TAF12 and ATF7 physically interact in OCLs. Knockdown of ATF7 in MVNP-expressing cells decreased cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1) induction by1,25-(OH)₂D₃, as well as TAF12 binding to the CYP24A1 promoter. These results show that ATF7 interacts with TAF12 and contributes to the hypersensitivity of OCL precursors to 1,25-(OH)₂D₃ in PD.
authors: Department of Medicine, Hematology Oncology, Indiana University, Indianapolis, IN, USA.
authors: Jumpei
authors: J
authors: Teramachi
authors: Yuko
authors: Y
authors: Hiruma
authors: Seiichi
authors: S
authors: Ishizuka
authors: Hisako
authors: H
authors: Ishizuka
authors: Jacques P
authors: JP
authors: Brown
authors: Laëtitia
authors: L
authors: Michou
authors: Huiling
authors: H
authors: Cao
authors: Deborah L
authors: DL
authors: Galson
authors: Mark A
authors: MA
authors: Subler
authors: Hua
authors: H
authors: Zhou
authors: David W
authors: DW
authors: Dempster
authors: Jolene J
authors: JJ
authors: Windle
authors: G David
authors: GD
authors: Roodman
authors: Noriyoshi
authors: N
authors: Kurihara
mesh_terms: D051696:Activating Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010001:Osteitis Deformans / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053245:RANK Ligand / Q000096:biosynthesis / Q000235:genetics; D020218:Response Elements; D013234:Stem Cells / Q000378:metabolism* / Q000473:pathology; D013250:Steroid Hydroxylases / Q000096:biosynthesis / Q000235:genetics; D035381:TATA-Binding Protein Associated Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000235:genetics; D065668:Vitamin D3 24-Hydroxylase
chemical_list: C427752:ATF7 protein, human; D051696:Activating Transcription Factors; D053245:RANK Ligand; C470012:TAF12 protein, human; D035381:TATA-Binding Protein Associated Factors; C505688:TNFSF11 protein, human; C505689:Tnfsf11 protein, mouse; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol