The p53/Retinoblastoma-mediated Repression of Testicular Orphan Receptor-2 in the Rhesus Monkey with Cryptorchidism

Mu, Xiaoli; Liu, Yi‐Xun; Collins, Loretta L.; Kim, Eungseok; Chang, Chawnshang

doi:10.1074/jbc.m910158199

Cited by 31 publications

(23 citation statements)

References 62 publications

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“…Northern and Western Blot Analysis-Total RNA was isolated and Northern blot was performed as described previously (30). E2F1 antibody (KH95) was purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA).…”

Section: Methodsmentioning

confidence: 99%

TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells

Chang

2003

Journal of Biological Chemistry

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Early studies suggested both TR3 orphan receptor (TR3) and apoptosis mediator E2F1 might play an important role in mediating prostate cancer cell apoptosis. Their linkage and relationship, however, remain unclear. Here we found that 12-O-tetradecanoylphorbol-13-acetate (TPA) could induce cell apoptosis via induction of TR3 and E2F1 expression in LNCaP prostate cancer cells. Addition of antisense E2F1 could partially rescue the TR3-mediated cell apoptosis, and transfection of the TR3 dominant-negative plasmid could block the TR3-induced E2F1 expression. These data suggest that TPA is able to induce LNCaP cell apoptosis via induction of TR3 resulting in the induction of E2F1. Promoter reporter assays show that TR3 can induce E2F1 expression via binding to the TR3 response element (TR3RE) in the E2F1 promoter ؊316 to ؊324 bp region. TR3 can bind specifically to this TR3RE with a K d of 6.29 nM, and mutations of this E2F1-TR3RE can partially block the TR3-mediated E2F1 expression. Taken together, these data suggest that TPA is able to induce cell apoptosis via a TPA 3 TR3 3 E2F1 3 apoptosis pathway in LNCaP cells. Further studies of how to modulate this pathway may allow us to better understand how to control the prostate cancer growth.Human TR3 orphan receptor, isolated by our laboratory (1), is the human homologue of mouse Nur-77 (2) and rat NGFIB (3, 4) genes. TR3

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Section: Methodsmentioning

confidence: 99%

TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells

Chang

2003

Journal of Biological Chemistry

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“…Despite the absence of putative ligands, TR2 has been reported to affect various cellular processes, including differentiation, proliferation, and apoptosis (4,(17)(18)(19). At the molecular level, TR2 can be an activator or a repressor for the same target genes that carry HREs, such as DR5 of Rar␤ (20) and DR1 of Oct4 (4).…”

mentioning

confidence: 99%

Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression

Gupta

Huq

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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We previously reported an intricate mechanism underlying the homeostasis of Oct4 expression in normally proliferating stem cell culture of P19, mediated by SUMOylation of orphan nuclear receptor TR2. In the present study, we identify a signaling pathway initiated from the nongenomic activity of all-trans retinoic acid (atRA) to stimulate complex formation of extracellular signal-regulated kinase 2 (ERK2) with its upstream kinase, mitogen-activated protein kinase kinase (MEK). The activated ERK2 phosphorylates threonine-210 (Thr-210) of TR2, stimulating its subsequent SUMOylation. Dephosphorylated TR2 recruits coactivator PCAF and functions as an activator for its target gene Oct4. Upon phosphorylation at Thr-210, TR2 increasingly associates with promyelocytic leukemia (PML) nuclear bodies, becomes SUMOylated, and recruits corepressor RIP140 to act as a repressor for its target, Oct4. To normally proliferating P19 stem cell culture, exposure to a physiological concentration of atRA triggers a rapid nongenomic signaling cascade to suppress Oct4 gene and regulate cell proliferation.

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“…Because Rb can be regulated via phosphorylation by cyclin-dependent kinase and loses its ability to block cell cycle progression when hyperphosphorylated, the cyclindependent kinase inhibitor p21 prevents the inactivation of Rb. Rb is then able to bind transcription factor E2F and reduce expression of TR2 (44). Although the possibility exists that alternative pathways may be present that result in p53-mediated regulation of TR2, the above described p53 3 p21 3 cyclin-dependent kinase 3 Rb 3 E2F 3 TR2 pathway may also occur in the context of HPV-16 infection and proliferation.…”

Section: Discussionmentioning

confidence: 99%

“…In a study examining the effect of both p53 and the retinoblastoma (Rb) protein on TR2 in the context of cryptorchidism, it was found that each tumor suppressor protein (p53 or Rb) had a repressive effect on TR2 expression (44). The known binding of proteins E6 and E7 to p53 and Rb, respectively, as well as the subsequent ubiquitin-mediated degradation of the tumor suppressor proteins known to result from such binding (36,(45)(46)(47) further implicated p53 and Rb as mediators of TR2 repression (44). The model proposed in the cryptorchidism study suggests that the down-regulation of TR2 by p53 involves a pathway in which p53 up-regulates one of its targets, p21.…”

Section: Discussionmentioning

confidence: 99%

Feedback Regulation between Orphan Nuclear Receptor TR2 and Human Papilloma Virus Type 16

Collins

Lin

et al. 2001

Journal of Biological Chemistry

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The human TR2 orphan receptor (TR2), initially isolated from testis and prostate cDNA libraries, is a member of the steroid receptor superfamily. TR2 can regulate several target genes via binding to a consensus response element (AGGTCA) in direct repeat orientation (AGGTCAX (n) AGGTCA, n ‫؍‬ 0 -6). Here we show that TR2 is able to induce the expression of human papilloma virus type 16 (HPV-16) genes via binding to a DR4 response element in the long control region of HPV-16. Additionally, one of the HPV-16 gene products, the E6 oncogene, regulates TR2 gene expression. A likely mechanism for this regulation involves E6-mediated degradation of the tumor suppressor p53, a protein known to suppress TR2 expression. Together our data provide evidence for feedback regulation between TR2 and HPV-16, which represents a novel regulatory pathway involving a member of the steroid receptor superfamily and the HPV-16 DNA tumor virus.Orphan receptors, or receptors without known ligands, make up the vast majority of members of the steroid receptor superfamily (1-3). Members of this family are characterized by a highly conserved DNA-binding domain (DBD) 1 and a carboxylterminal ligand-binding domain. The conserved amino acid sequence within the DBDs of these receptors is predicted to form two zinc finger motifs (1). Additionally, steroid receptors bind to specific DNA sequences known as hormone response elements (HREs) through which regulation of target gene expression may occur (1). The cDNA of the human TR2 orphan receptor (TR2) was isolated from the screening of human testis and prostate cDNA libraries for the androgen receptor. In the screening, an oligonucleotide probe homologous to the highly conserved DBD of the glucocorticoid receptor was used (2). Four TR2 cDNA clones (TR2-5, -7, -9, and -11) were isolated and found to share identical sequences in the N-terminal and DBD regions yet were found to differ in the length of the C-terminal putative ligand-binding domain (3).Through further study of TR2, it was found that this orphan receptor binds to a consensus HRE composed of a direct repeat (DR) with variable spacing (AGGTCAX (n) AGGTCA, n ϭ 0 -6) (4). Using the known TR2 HRE sequence as a guide, it was determined that TR2 has modulatory effects on several signaling pathways such as those involving retinoic acid (4), thyroid hormone (5), and ciliary neurotrophic factor (6). Moreover, expression of the erythropoietin gene (7), aldolase gene (8), histamine H1 receptor (9), and simian virus 40 (SV40) (10) is also regulated by TR2. To add to the list of TR2-responsive genes, we have found a TR2 DR4 consensus site within the long control region (LCR) of the human papilloma virus type 16 (HPV-16). In this report, we show that TR2 is able to bind the consensus response element (DR4RE) within the HPV-16 gene and modulate HPV-16 expression. The human papilloma virus is a common sexually transmitted pathogen that is linked to increased risk for the development of cervical neoplasia, one of the most common cancers in women throughou...

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The p53/Retinoblastoma-mediated Repression of Testicular Orphan Receptor-2 in the Rhesus Monkey with Cryptorchidism

Cited by 31 publications

References 62 publications

TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells

TR3 Orphan Nuclear Receptor Mediates Apoptosis through Up-regulating E2F1 in Human Prostate Cancer LNCaP Cells

Retinoic acid-stimulated sequential phosphorylation, PML recruitment, and SUMOylation of nuclear receptor TR2 to suppress Oct4 expression

Feedback Regulation between Orphan Nuclear Receptor TR2 and Human Papilloma Virus Type 16

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