Protein-binding properties of 22-oxa-1.ALPHA.,25-dihydroxyvitamin D3, a synthetic analogue of 1.ALPHA.,25-dyhydroxyvitamin D3.

Okano, Toshio; Tsugawa, Naoko; Masuda, Sonoko; Takeuchi, Atsuko; Kobayashi, Tadashl; Nishii, Yasuho

doi:10.3177/jnsv.35.529

Cited by 72 publications

(31 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There is some controversy concerning the OCT receptor. It has been demonstrated that the binding of OCT to its receptor is lower than that of 1,25(OH)2D3 [27,28] although OCT is more potent than 1,25(OH)2D3 [13,29]. The reason for this discrepancy is unclear.…”

Section: Discussionmentioning

confidence: 57%

Effect of 22-Oxa-1,25-Dihydroxyvitamin D3 on Human Thyroid Cancer Cell Growth.

et al. 1999

View full text Add to dashboard Cite

Abstract.To examine whether synthetic vitamin D3 analog, 22-oxa-1,25(OH)2D3 (OCT) has an inhibitory effect on the growth of thyroid carcinoma, we tested the in vitro and in vivo effects of OCT on the growth of a welldifferentiated thyroid cancer cell line, NPA. OCT bound to its receptor at the same rate as 1,25(OH)2D3, and inhibited the proliferation of NPA cells in vitro in a dose-dependent manner, similar to that observed with 1,25(OH)2D3. Northern blot analysis showed that steady-state and fetal bovine serum-stimulated levels of c-myc mRNA were suppressed after 0.5-4 hour treatment with OCT. Transfection studies with the deletion mutants of the 5"-up-stream flanking region of c-myc/chroramphenicol acetyltransferase chimera genes indicated the presence of an OCT responsive element between -410 and -106. Next, we examined OCT effects in implanted NPA tumor cells in nude mice. OCT showed no remarkable hypercalcemic effect compared to 1, 25 (0H2)D3, but OCT and 1, 25 (OH2)D3, had no significant inhibitory effect in vivo after either intra-tumor or intra-peritoneum injection. Our results demonstrate that OCT inhibits the proliferation of well-differentiated thyroid cancer in an in vitro system associated with the suppression of c-myc mRNA, but this inhibitory effect was not reproducible in in vivo model.

show abstract

Section: Discussionmentioning

confidence: 57%

Effect of 22-Oxa-1,25-Dihydroxyvitamin D3 on Human Thyroid Cancer Cell Growth.

et al. 1999

View full text Add to dashboard Cite

show abstract

“…Therefore, it was of interest to determine whether the synergistic action of 1␣-25-(OH) 2 D 3 toward AP-1 transcriptional activity in TGF-␤1-treated cells was VDR-dependent or -independent. In this regard, some studies (34,49) have shown that OCT, a 1␣-25-(OH) 2 D 3 derivative, has a high affinity for VDR and that its biological activity is generated via the VDR-dependent (genomic) pathway. In contrast, 24,25-(OH) 2 D 3 is an analog that has very low affinity for VDR (29,49).…”

Section: Effect Of 1␣-25-(oh) 2 D 3 Analogs On Tgf-␤1-induced Ap-1 Trmentioning

confidence: 99%

“…In this regard, some studies (34,49) have shown that OCT, a 1␣-25-(OH) 2 D 3 derivative, has a high affinity for VDR and that its biological activity is generated via the VDR-dependent (genomic) pathway. In contrast, 24,25-(OH) 2 D 3 is an analog that has very low affinity for VDR (29,49). Therefore, using these two analogs, we exam- Ϫ8 M in serum-free ␣-MEM.…”

Section: Effect Of 1␣-25-(oh) 2 D 3 Analogs On Tgf-␤1-induced Ap-1 Trmentioning

confidence: 99%

1α,25-Dehydroxyvitamin D3 Synergism toward Transforming Growth Factor-β1-induced AP-1 Transcriptional Activity in Mouse Osteoblastic Cells via Its Nuclear Receptor

Takeshita¹,

Imai²,

Kato³

et al. 1998

Journal of Biological Chemistry

View full text Add to dashboard Cite

TGF-␤11 is locally produced by osteoblasts and accumulates abundantly in bone matrix tissue (1-3). This local cytokine plays an important role as a "coupling factor" in bone remodeling (4 -7). We (8, 9) previously demonstrated that TGF-␤1 is a potent activator of AP-1, a transcriptional factor that is a heterodimer of FOS and JUN proteins, in mouse osteoblastic MC3T3-E1 cells. AP-1 activates the transcription of target genes by binding to specific promoter elements called TRE. In fact, several studies (10 -16) have suggested that AP-1 is a regulatory factor in bone metabolism. Therefore, it is of interest to investigate the mechanism by which AP-1 regulates the metabolism of TGF-␤1-treated bone cells, which regulation may occur in an autocrine and/or paracrine fashion.1␣-25-(OH) 2 D 3 also is an important systemic hormone in bone metabolism and regulates transcriptionally the expression of several genes involved in the differentiation of osteoblastic cells (17)(18)(19)(20)(21)(22)(23). Many studies (20 -26) have shown that the hormone binds to its receptor, VDR, in the cell nucleus and acts via binding of this complex to the VDR response element. This VDR-dependent action is referred to as the "genomic action" of the hormone. On the other hand, other recent studies (27-37) have suggested that the hormone is also able to induce several biological activities via protein kinase C, ceramide signaling pathways, and via an increase in the intracellular calcium concentration, which are called "nongenomic action."Several investigators (21-24) have demonstrated negative regulation between AP-1 and VDR of the transcriptional activity of osteocalcin and collagen genes, both of which are involved in bone formation. However, positive regulation by 1␣-25-(OH) 2 D 3 of AP-1 transcriptional activity in osteoblastic cells has not been demonstrated in detail. Therefore, it is of interest to explore the possibility of 1␣-25-(OH) 2 D 3 positive regulation of AP-1 transcriptional activity via "genomic" or "nongenomic" action.In this regard, we investigated in the present study the regulation by 1␣-25-(OH) 2 D 3 of TGF-␤1-induced AP-1 transcriptional activity in osteoblastic MC3T3-E1 cells. As a result, we demonstrated the presence of 1␣-25-(OH) 2 D 3 synergism toward TGF-␤1-induced AP-1 transcriptional activity via genomic action. This demonstration suggests the presence of a novel positive regulation by 1␣-25-(OH) 2 D 3 of AP-1 transcriptional activity in osteoblastic cells via the VDR-dependent pathway (genomic action). MATERIALS AND METHODSReagents-Human recombinant TGF-␤1 was purified to homogeneity (Ͼ98.9%, determined by SDS-polyacrylamide gel electrophoresis analysis: King Brewer, Kakogawa, Japan). 1␣-25-(OH) 2 D 3 , 24,25-(OH) 2 D 3 , and 22-oxa-1,25-dihydroxyvitamin D 3 (OCT) were kindly provided by Chugai Pharmaceutical Co., Ltd. (Tokyo, Japan). ␣-MEM was obtained from Flow Laboratories (McLean, VA). FCS was from HyClone (Logan, UT). 5Ј-[␣-32 P]dCTP megaprime DNA labeling system and [␥-32 P]ATP were purchased from Amersham...

show abstract

“…Moreover, altered pharmacokinetics may also explain the enhanced antiproliferative effects since the analog will quickly reach high peak levels in target tissues compared with the slow rise and drop of 1,25(OH) 2 D 3 . Maxacalcitol has a short half-life due to 500 times lower affinity to DBP (341). Eldecalcitol on the contrary has a fourfold stronger affinity for DBP than 1,25(OH) 2 D 3 (381) which results in longer sustained plasma levels than 1,25(OH) 2 D 3 .…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Christakos

Dhawan

Verstuyf

et al. 2016

Physiological Reviews

1,358

1,234

View full text Add to dashboard Cite

, [1,25(OH) 2 D 3 ] is the hormonally active form of vitamin D. The genomic mechanism of 1,25(OH) 2 D 3 action involves the direct binding of the 1,25(OH) 2 D 3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Numerous VDR co-regulatory proteins have been identified, and genome-wide studies have shown that the actions of 1,25(OH) 2 D 3 involve regulation of gene activity at a range of locations many kilobases from the transcription start site. The structure of the liganded VDR/RXR complex was recently characterized using cryoelectron microscopy, X-ray scattering, and hydrogen deuterium exchange. These recent technological advances will result in a more complete understanding of VDR coactivator interactions, thus facilitating cell and gene specific clinical applications. Although the identification of mechanisms mediating VDR-regulated transcription has been one focus of recent research in the field, other topics of fundamental importance include the identification and functional significance of proteins involved in the metabolism of vitamin D. CYP2R1 has been identified as the most important 25-hydroxylase, and a critical role for CYP24A1 in humans was noted in studies showing that inactivating mutations in CYP24A1 are a probable cause of idiopathic infantile hypercalcemia. In addition, studies using knockout and transgenic mice have provided new insight on the physiological role of vitamin D in classical target tissues as well as evidence of extraskeletal effects of 1,25(OH) 2 D 3 including inhibition of cancer progression, effects on the cardiovascular system, and immunomodulatory effects in certain autoimmune diseases. Some of the mechanistic findings in mouse models have also been observed in humans. The identification of similar pathways in humans could lead to the development of new therapies to prevent and treat disease.

show abstract

Protein-binding properties of 22-oxa-1.ALPHA.,25-dihydroxyvitamin D3, a synthetic analogue of 1.ALPHA.,25-dyhydroxyvitamin D3.

Cited by 72 publications

References 6 publications

Effect of 22-Oxa-1,25-Dihydroxyvitamin D3 on Human Thyroid Cancer Cell Growth.

Effect of 22-Oxa-1,25-Dihydroxyvitamin D3 on Human Thyroid Cancer Cell Growth.

1α,25-Dehydroxyvitamin D3 Synergism toward Transforming Growth Factor-β1-induced AP-1 Transcriptional Activity in Mouse Osteoblastic Cells via Its Nuclear Receptor

Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects

Contact Info

Product

Resources

About