AP-1 and Vitamin D Receptor (VDR) Signaling Pathways Converge at the Rat Osteocalcin VDR Element: Requirement for the Internal Activating Protein-1 Site for Vitamin D-Mediated Trans-Activation**This work was supported by NIH Grants AR-45689, AR-39588, and DE-12528. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.

Aslam, Fauzia; McCabe, Laura R.; Frenkel, Baruch; Wijnen, André J. van; Stein, Gary S.; Lian, Jane B.; Stein, Janet L.

doi:10.1210/endo.140.1.6429

Cited by 35 publications

(15 citation statements)

References 45 publications

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“…Notwithstanding that AP1 family members are differentially expressed during osteoblast differentiation (26), AP1 binding sites have been identified in the promoter of several genes expressed in osteoblasts, where they often mediate the responsiveness of these promoters to growth factors (27)(28)(29). More recently, the role of AP1 family members has been emphasized in vivo by two studies showing respectively that Fra1 or ⌬FosB overexpression in mice enhanced bone formation by osteoblasts and led to osteosclerosis (25,30).…”

Section: Discussionmentioning

confidence: 99%

Characterization of an Osteoblast-specific Enhancer Element in the CBFA1 Gene

Zambotti

Makhluf²,

Shen³

et al. 2002

Journal of Biological Chemistry

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Cbfa1 is a critical regulator of cell differentiation expressed only in the osteochondrogenic lineage. To define the molecular basis of this cell-specific expression we analyzed the murine Cbfa1 promoter. Here we show that the first 976 bp of this promoter are specifically active in osteoblastic cells. Within this region DNase I footprinting delineated a 40-bp area (CE1) protected differently by nuclear extracts from osteoblastic cells and from non-osteoblastic cells. When multimerized, CE1 conferred an osteoblast-specific activity to a heterologous promoter in DNA transfection experiments; this enhancing ability was conserved between mouse, rat, and human CE1 present in the respective Cbfa1 promoters. CE1 site-specific mutagenesis determined that it binds NF1-and AP1-like activities. Further analyses revealed that the NF1 site acts as a repressor in nonosteoblastic cells due to the binding of NF1-A, a NF1 isoform not expressed in osteoblastic cells. In contrast, the AP1 site mediates an osteoblast-specific activation caused by the preferential binding of FosB to CE1 in osteoblastic cells. In summary, this study identified an osteoblast-specific enhancer in the Cbfa1 promoter whose activity is achieved by the combination of an inhibitory and an activatory mechanism.

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Section: Discussionmentioning

confidence: 99%

Characterization of an Osteoblast-specific Enhancer Element in the CBFA1 Gene

Zambotti

Makhluf²,

Shen³

et al. 2002

Journal of Biological Chemistry

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“…For instance, interactions between Runx2 and Cbf␤ were essential for normal bone formation in vivo (11)(12)(13). Likewise, interactions between Runx2 and Rb protein or TAZ protein were found to induce osteoblast differentiation (20,22). Runx2 activity can also be negatively regulated via this mechanism.…”

Section: Fig 4 Atf4 and Runx2 Cooperatively Activate Ocn Transcriptmentioning

confidence: 99%

“…Runx2 expression and functional activity are controlled by a number of factors, including bone morphogenetic proteins, fibroblast growth factor-2, PTH, 1 tumor necrosis factor-␣, and extracellular matrix signals (5)(6)(7)(8)(9)(10). Runx2 can also physically interact with a number of nuclear proteins, including Cbf␤, which forms heterodimers with all members of the Cbfa/Runx family of factors (11)(12)(13), the transcriptional co-repressor TLE/Groucho and its antagonist, HES-1 (14,15), AP-1 proteins (16 -18), SMADs (19), the retinoblastoma tumor suppressor (Rb protein) (20), Stat1 (21), TAZ (transcriptional co-activator with PDZ-binding motif) (22), lymphoid enhancer factor 1 (LEF1) (23), and Twist (24).…”

mentioning

confidence: 99%

Cooperative Interactions between Activating Transcription Factor 4 and Runx2/Cbfa1 Stimulate Osteoblast-specific Osteocalcin Gene Expression

Xiao

Jiang

et al. 2005

Journal of Biological Chemistry

220

203

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(2004) Cell 117, 387-398). However, the mechanisms of ATF4 in bone cells are still not clear. In this study, we determined the molecular mechanisms through which ATF4 activates the mouse osteocalcin (Ocn) gene 2 (mOG2) expression and mOG2 promoter activity. ATF4 increased the levels of Ocn mRNA and mOG2 promoter activity in Runx2-containing osteoblasts but not in non-osteoblastic cells that lack detectable Runx2 protein. However, ATF4 increased Ocn mRNA and mOG2 promoter activity in non-osteoblastic cells when Runx2 was co-expressed. Mutational analysis of the OSE1 (ATF4-binding site) and the two OSE2s (Runx2-binding sites) in the 657-bp mOG2 promoter demonstrated that ATF4 and Runx2 activate Ocn via cooperative interactions with these sites. Pull-down assays using nuclear extracts from osteoblasts or COS-7 cells overexpressing ATF4 and Runx2 showed that both factors are present in either anti-ATF4 and anti-Runx2 immunoprecipitates. In contrast, pull-down assays using purified glutathione S-transferase fusion proteins were unable to demonstrate a direct physical interaction between ATF4 and Runx2. Thus, accessory factors are likely involved in stabilizing interactions between these two molecules. Regions within Runx2 required for ATF4 complex formation and activation were identified. Deletion analysis showed that the leucine zipper domain of ATF4 is critical for Runx2 activation. This study is the first demonstration that cooperative interactions between ATF4 and Runx2/Cbfa1 stimulate osteoblast-specific Ocn expression and suggests that this regulation may represent a novel intramolecular mechanism regulating Runx2 activity and, thereby, osteoblast differentiation and bone formation.

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“…1,25D exerts most of its biological actions through VDR, which acts as a transcription factor (MacDonald et al 2001). VDR bound to 1,25D and retinoid X receptor interacts with vitamin D-response elements (VDREs) in the promoters of vitamin D target genes (Aslam et al 1999). In this regard, it is known that the VDR interacts with co-repressors as part of the transcriptional mechanisms by which myoblast arrest is induced (Campbell 2014).…”

Section: Introductionmentioning

confidence: 99%

Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells

Irazoqui¹,

Boland²,

Buitrago³

2014

Journal of Molecular Endocrinology

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Previously, we have reported that 1,25(OH) 2 -vitamin D 3 (1,25D) activates p38 MAPK (p38) in a vitamin D receptor (VDR)-dependent manner in proliferative C2C12 myoblast cells. It was also demonstrated that 1,25D promotes muscle cell proliferation and differentiation. However, we did not study these hormone actions in depth. In this study we have investigated whether the VDR and p38 participate in the signaling mechanism triggered by 1,25D. In C2C12 cells, the VDR was knocked down by a shRNA, and p38 was specifically inhibited using SB-203580. Results from cell cycle studies indicated that hormone stimulation prompts a peak of S-phase followed by an arrest in the G0/G1-phase, events which were dependent on VDR and p38. Moreover, 1,25D increases the expression of cyclin D3 and the cyclin-dependent kinase inhibitors, p21Waf1/Cip1 and p27 Kip1 , while cyclin D1 protein levels did not change during G0/G1 arrest. In all these events, p38 and VDR were required. At the same time, a 1,25D-dependent acute increase in myogenin expression was observed, indicating that the G0/G1 arrest of cells is a pro-differentiative event. Immunocytochemical assays revealed co-localization of VDR and cyclin D3, promoted by 1,25D in a p38-dependent manner. When cyclin D3 expression was silenced, VDR and myogenin levels were downregulated, indicating that cyclin D3 was required for 1,25D-induced VDR expression and the concomitant entrance into the differentiation process. In conclusion, the VDR and p38 are involved in control of the cellular cycle by 1,25D in skeletal muscle cells, providing key information on the mechanisms underlying hormone regulation of myogenesis.

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Cited by 35 publications

References 45 publications

Characterization of an Osteoblast-specific Enhancer Element in the CBFA1 Gene

Characterization of an Osteoblast-specific Enhancer Element in the CBFA1 Gene

Cooperative Interactions between Activating Transcription Factor 4 and Runx2/Cbfa1 Stimulate Osteoblast-specific Osteocalcin Gene Expression

Actions of 1,25(OH)2-vitamin D3 on the cellular cycle depend on VDR and p38 MAPK in skeletal muscle cells

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