Ternary Complexes and Cooperative Interplay between NCoA-62/Ski-interacting Protein and Steroid Receptor Coactivators in Vitamin D Receptor-mediated Transcription

Zhang, Chi; Baudino, Troy A.; Dowd, Diane R.; Tokumaru, Hisashi; Wang, Wen; MacDonald, Paul N.

doi:10.1074/jbc.m106263200

Cited by 65 publications

(68 citation statements)

References 39 publications

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“…Helix H10 mutation also attenuated VDR transactivation function, presumably as a result of disrupted interactions not only with TFIIB and RXR, but also with SKIP/NCoA-62. Wild type VDR interacted with SKIP/NCoA-62 in both the absence and presence of 1,25(OH) 2 D 3 , whereas its interaction with TFIIB was partially inhibited and with RXR was augmented by 1,25(OH) 2 D 3 , consistent with earlier reports (5,7,13).…”

Section: Vdr Helix H10 Mutations Inhibit Transactivation Function-effsupporting

confidence: 82%

“…SKIP/NCoA-62 forms a ternary complex and acts synergistically with the p160 coactivator GRIP1 to augment VDR transactivation (13). Consistent with such complex formation, p160 coactivators contact VDR through the AF-2 do-main, whereas SKIP/NCoA-62 interactions with VDR are AF-2-independent.…”

Section: The Vitamin D Receptor (Vdr)mentioning

confidence: 65%

“…SKIP/NCoA-62 reportedly contacts helix H1 of the VDR LBD (residues 116 -164 of human VDR) and the helix H10/H11 region (residues 373-403) but not helix H12 (7). It was subsequently shown, however, that SKIP/NCoA-62 could bind to the VDR:RXR heterodimer, leading to the conclusion that the heterodimerization interface (including helix H10/ H11) could be excluded as a SKIP/NCoA-62 interaction surface (13).…”

Section: The Vitamin D Receptor (Vdr)mentioning

confidence: 99%

“…SKIP/NCoA-62 augments transactivation by the vitamin D, retinoic acid, estrogen, and glucocorticoid receptors (7), selectively binding the VDR:RXR heterodimer in a ligand-enhanced manner (13). SKIP/NCoA-62 forms a ternary complex and acts synergistically with the p160 coactivator GRIP1 to augment VDR transactivation (13).…”

Section: The Vitamin D Receptor (Vdr)mentioning

confidence: 99%

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Interactions of SKIP/NCoA-62, TFIIB, and Retinoid X Receptor with Vitamin D Receptor Helix H10 Residues

Barry¹,

Leong²,

Church³

et al. 2003

Journal of Biological Chemistry

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The vitamin D receptor (VDR) is a ligand-dependent transcription factor that heterodimerizes with retinoid X receptor (RXR) and interacts with the basal transcription machinery and transcriptional cofactors to regulate target gene activity. The p160 coactivator GRIP1 and the distinct coregulator Ski-interacting protein (SKIP)/NCoA-62 synergistically enhance ligand-dependent VDR transcriptional activity. Both coregulators bind directly to and form a ternary complex with VDR, with GRIP1 contacting the activation function-2 (AF-2) domain and SKIP/NCoA-62 interacting through an AF-2 independent interface. It was previously reported that SKIP/NCoA-62 interaction with VDR was independent of the heterodimerization interface (specifically, helices H10/H11). In contrast, the present study defines specific residues within a conserved and surface-exposed region of VDR helix H10 that are required for interaction with SKIP/NCoA-62 and for full ligand-dependent transactivation activity. SKIP/NCoA-62, the basal transcription factor TFIIB, and RXR all interacted with VDR helix H10 mutants at reduced levels compared with wild type in the absence of ligand and exhibited different degrees of increased interaction upon ligand addition. Thus, SKIP/ NCoA-62 interacts with VDR at a highly conserved region not previously associated with coregulator binding to regulate transactivation by a molecular mechanism distinct from that of p160 coactivators. The vitamin D receptor (VDR)1 is a ligand-dependent transcription factor important in the regulation of calcium homeostasis, development, cell growth, and differentiation. VDR belongs to the nuclear receptor superfamily, members of which share a common modular structure including a highly conserved DNA binding domain (DBD) and a conserved ligand binding domain (LBD). The LBD has a predominantly ␣-helical structure with an activation function-2 (AF-2) domain in the COOH-terminal helix (H12). The LBD is the main site of VDR interaction with its heterodimer partner retinoid X receptor (RXR) and basal transcription factors, and the AF-2 domain in combination with the hydrophobic cleft forms an interaction surface for transcriptional corepressors and coactivators (1, 2). In the absence of its ligand 1,25-dihydroxyvitamin D 3

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Section: Vdr Helix H10 Mutations Inhibit Transactivation Function-effsupporting

confidence: 82%

Section: The Vitamin D Receptor (Vdr)mentioning

confidence: 65%

Section: The Vitamin D Receptor (Vdr)mentioning

confidence: 99%

Section: The Vitamin D Receptor (Vdr)mentioning

confidence: 99%

See 2 more Smart Citations

Interactions of SKIP/NCoA-62, TFIIB, and Retinoid X Receptor with Vitamin D Receptor Helix H10 Residues

Barry¹,

Leong²,

Church³

et al. 2003

Journal of Biological Chemistry

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“…Recent studies demonstrate that SkiP interacts with many transcriptional regulators to modulate transcription. Some of the SkiP partners recently identified include NotchIC (Zhou et al, 2000), Smad proteins (Leong et al, 2001), retinoblastoma tumor suppressor (Prathapam et al, 2002), vitamin D receptor (VDR) (Zhang et al, 2001), N-CoR/SMRT, and p300 (Leong et al, 2004). Increased SKIIP expression has been found to enhance gene expression mediated by vitamin D, retinoic acid, estrogen, and glucocorticoid (Baudino …”

Section: Estrogen-regulated Genes Expression In Ovarian Cancer Cells mentioning

confidence: 99%

Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells

et al. 2005

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Estrogens regulate normal ovarian surface epithelium (OSE) cell functions but also affect epithelial ovarian cancer (OCa) development. Little is known about how estrogens play such opposing roles. Transcriptional profiling using a cDNA microarray containing 2400 named genes identified 155 genes whose expression was altered by estradiol-17b (E2) in three immortalized normal human ovarian surface epithelial (HOSE) cell lines and 315 genes whose expression was affected by the hormone in three established OCa (OVCA) cell lines. All but 19 of the genes in these two sets were different. Among the 19 overlapping genes, five were found to show discordant responses between HOSE and OVCA cell lines. The five genes are those that encode clone 5.1 RNAbinding protein (RNPS1), erythrocyte adducin a subunit (ADD1), plexin A3 (PLXNA3 or the SEX gene), nuclear protein SkiP (SKIIP), and Rap-2 (rap-2). RNPS1, ADD1, rap-2, and SKIIP were upregulated by E2 in HOSE cells but downregulated by estrogen in OVCA cells, whereas PLXNA3 showed the reverse pattern of regulation. The estrogen effects was observed within 6-18 h of treatment. In silicon analyses revealed presence of estrogen response elements in the proximal promoters of all five genes. RNPS1, ADD1, and PLXNA3 were underexpressed in OVCA cell lines compared to HOSE cell lines, while the opposite was true for rap-2 and SKIIP. Functional studies showed that RNPS1 and ADD1 exerted multiple antitumor actions in OVCA cells, while PLXNA3 only inhibited cell invasiveness. In contrast, rap-2 was found to cause significant oncogenic effects in OVCA cells, while SKIIP promotes only anchorageindependent growth. In sum, gene profiling data reveal that (1) E2 exerts different actions on HOSE cells than on OVCA cells by affecting two distinct transcriptomes with few overlapping genes and (2) among the overlapping genes, a set of putative oncogenes/tumor suppressors have been identified due to their differential responses to E2 between the two cell types. These findings may explain the paradoxical roles of estrogens in regulating normal and malignant OSE cell functions.

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New insights into the mechanisms of vitamin D action

Christakos

Dhawan

Liu

et al. 2003

J of Cellular Biochemistry

281

237

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The biologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is a secosteroid whose genomic mechanism of action is similar to that of other steroid hormones and is mediated by stereospecific interaction of 1,25(OH)(2)D(3) with the vitamin D receptor (VDR) which heterodimerizes with the retinoid X receptor (RXR). After interaction with the vitamin D response element (VDRE) in the promoter of target genes, transcription proceeds through the interaction of VDR with coactivators and with the transcription machinery. The identification of the steps involved in this process has been a major focus of recent research in the field. However, the functional significance of target proteins as well as the functional significance of proteins involved in the transport and metabolism of vitamin D is also of major importance. Within the past few years much new information has been obtained from studies using knockout and transgenic mice. New insight has been obtained using this technology related to the physiological significance of the vitamin D binding protein (DBP), used to transport vitamin D metabolites, as well as the physiological significance of target proteins including 25-hydroxyvitamin D(3) 24-hydroxylase (24(OH)ase), 25-hydroxyvitamin D(3)-1 alpha-hydroxylase (1 alpha-(OH)ase), VDR, and osteopontin. The crystal structure of the DBP and the ligand binding domain of the VDR have recently been reported, explaining, in part, the unique properties of these proteins. In addition novel 1,25(OH)(2)D(3) target genes have been identified including the epithelial calcium channel, present in the proximal intestine and in the distal nephron. Thus in recent years a number of exciting discoveries have been made that have enhanced our understanding of mechanisms involved in the pleiotropic actions of 1,25(OH)(2)D(3).

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Ternary Complexes and Cooperative Interplay between NCoA-62/Ski-interacting Protein and Steroid Receptor Coactivators in Vitamin D Receptor-mediated Transcription

Cited by 65 publications

References 39 publications

Interactions of SKIP/NCoA-62, TFIIB, and Retinoid X Receptor with Vitamin D Receptor Helix H10 Residues

Interactions of SKIP/NCoA-62, TFIIB, and Retinoid X Receptor with Vitamin D Receptor Helix H10 Residues

Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells

New insights into the mechanisms of vitamin D action

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