The role of RAR and RXR activation in retinoid-induced tissue factor suppression

Tenno, Taavo; Botling, Johan; Öberg, Fredrik; Jossan, S. S.; Nilsson, Kenneth; Siegbahn, Agneta

doi:10.1038/sj.leu.2401785

Cited by 8 publications

(8 citation statements)

References 37 publications

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“…Previous studies have shown that constitutive TF expression is suppressed by ATRA in the APL cell line NB4 and in monoblastic U-937 cells (16). However, we have found differences in suppression kinetics and in nuclear receptor activation requirements (3,17), suggesting that the mechanisms of suppression of TF expression differ between these cells. The transcriptional mechanisms of constitutive TF expression and its ATRA-induced suppression in APL cells and the potential role played by the PML/RARα fusion protein are, however, not known.…”

Section: Introductionmentioning

confidence: 74%

“…Cell culture NB4 cells, established from human acute promyelocytic leukemia (18), and human monoblastic cell line U-937 (19) possessed basal procoagulant activity and expressed TF antigen and mRNA which was down-regulated by retinoids (3,17). U-937 cells expressing PML/RARα fusion protein under control of the Zn-inducible MT-1 promoter, U-937MTPR#9 (20) (a kind gift from Dr. P.G.…”

Section: Methodsmentioning

confidence: 99%

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PML/RARα plays a role for basal activity and retinoid-induced repression of the tissue factor promoter in acute promyelocytic leukemia cells

et al. 2003

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Constitutive expression of tissue factor (TF) by acute promyelocytic leukemia (APL) cells may contribute to thrombotic complications. In this study we examined the transcriptional mechanisms of all-trans retinoic acid (ATRA)-induced down-regulation of TF in the APL cell line NB4, by analysis of stable clones expressing the luciferase gene under the control of 5' flanking regions of the TF gene. We show that the TF promoter is constitutively active in NB4 cells, and that ATRA induces rapid suppression of the promoter. Basal activity and ATRA-induced suppression of TF promoter is determined by the proximal -383 to +121 bp of the promoter. Electrophoretic mobility shift assays demonstrate the binding of Fos/Jun complexes to two TF promoter AP-1 sites in this region. Both complexes were suppressed by ATRA treatment. The ectopic expression of the APL-specific PML/RARalpha oncoprotein in U-937 cells results in induction of TF mRNA and promoter activity. Interestingly, this PML/RARalpha-mediated increase in TF promoter activity is sensitive to ATRA treatment. These data indicate that TF expression in APL cells is exacerbated by the presence of the PML/RARalpha fusion protein, and implicates the loss of Fos/Jun binding to the TF promoter in ATRA-induced suppression of TF.

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Section: Introductionmentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

PML/RARα plays a role for basal activity and retinoid-induced repression of the tissue factor promoter in acute promyelocytic leukemia cells

et al. 2003

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“…Due to estrogen suppression of Aldh1a2 and Aldh1a3 expression [31], cells with low Aldh1a1 expression or activity have diminished RA production [28]. RA inhibits tissue factor expression in endothelial and leukemic cell cultures, probably via RAR/RXR dependent mechanisms [53,54]. However, RA also directly regulates expression of RAR receptors [55] and required for the differentiation of lymphatic vasculature [56], that expect to be impaired in Aldh1a1 −/− females.…”

Section: Discussionmentioning

confidence: 99%

Moderate vitamin A supplementation in obese mice regulates tissue factor and cytokine production in a sex-specific manner

Gushchina

Yasmeen

Ziouzenkova

2013

Archives of Biochemistry and Biophysics

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Vitamin A (vitA) regulates obesity, insulin resistance, inflammation, dyslipidemia, and hemostasis through its metabolites retinaldehyde (Rald) and retinoic acid (RA) produced in endogenous enzymatic reactions. Combination of at least 3 of these conditions leads to development of metabolic syndrome (Msyn) and, consequently, type 2 diabetes and/or cardiovascular disease. Although many foods are fortified with vitA, it remains unknown what conditions of Msyn are influenced by moderate dietary vitA supplementation. A family of aldehyde dehydrogenase 1 (Aldh1) enzymes is a key contributor to obesity via sex- and fat depot-specific production of RA in adipose tissue. Therefore, we studied effects of moderate vitamin A supplementation of an obesogenic high-fat (HF) diet (4IU vitA/g and 20IU vitA/g HF diet) on multiple conditions and mediators of Msyn in wild-type (WT, C57Bl/6) and Aldh1a1−/− mice. We found that mild vitamin A supplementation did not influence obesity, fat distribution, and glucose tolerance in males and females of the same genotype. In contrast, multiplex analysis of bioactive proteins in blood showed moderately increased concentrations (10-15%) of inflammatory IL-18 and MIP-1γ in vitA supplemented vs. control WT males. Marked decrease (28-31%) in concentrations of lymphotactin and tissue factor, a key protein contributing to thrombogenesis during injury, was achieved by vitA supplementation in WT females compared to control WT females. Aldh1a1 deficiency reduced obesity, insulin resistance, suppressed many pro-inflammatory cytokines, and abolished the effects of vitA supplementation seen in WT mice. Our study revealed specific inflammatory and pro-thrombotic proteins in plasma regulated by dietary vitamin A and the critical role of endogenous vitA metabolism in these processes. The sex-specific decrease of plasma tissue factor concentrations by moderate dietary vitA supplementation could potentially reduce related pro-thrombotic states in obese females.

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“…Although the present study could not prove the mechanism by which TF promotes tumor invasion, our finding of a distinct association between TF and tumor invasiveness may have therapeutic as well as prognostic implications. Since retinoic acid (39), resveratol (40), vitamin D 3 (41), and pentoxifylline (42) have all been reported to down-regulate TF, the effects of these agents on TF expression in pancreatic cancer cells are worth evaluating. Recently, the relationship between TF expression and angiogenesis in various types of malignancies has also been emphasized (43 -45); this may occur through regulation of the vascular endothelial growth factor (46).…”

Section: Tissue Factor In Pancreatic Ductal Adenocarcinomamentioning

confidence: 99%

Prognostic Significance of Tissue Factor in Pancreatic Ductal Adenocarcinoma

Nitori

Ino²,

Nakanishi³

et al. 2005

Clinical Cancer Research

150

104

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Tissue factor (TF) is a transmembrane glycoprotein that plays roles in the blood coagulation and intracellular signaling pathways, and has also been suggested to modulate the biological behavior of cancer cells. In order to examine the clinicopathologic significance of TF expression in pancreatic ductal adenocarcinoma, TF expression was determined by immunohistochemistry using a newly raised anti-TF monoclonal antibody in 113 patients who had undergone surgical resection of pancreatic ductal adenocarcinoma. According to the incidence of tumor cell immunopositivity, patients were divided into ''negative TF'' (0%), ''weak TF'' (<25%), or ''high TF'' (25% or more) groups, which accounted for 11.6% (n = 13), 44.2% (n = 50), and 44.2% (n = 50) of the total, respectively. Increased TF expression was correlated with the extent of the primary tumor (P = 0.0043), lymph node metastasis (P = 0.0043), lymphatic distant metastasis (P = 0.0039), advanced tumor-node-metastasis stage (P = 0.0002), and high tumor grade (P = 0.0164). Multivariate analysis using the Cox proportional hazards model showed that high TF expression was an independent negative predictor for survival (hazard ratio, 2.014; P = 0.0076). Moreover, patients with TF-negative tumors had a significantly better prognosis even if lymph node metastasis was present (P < 0.0001). We also showed that TF knockdown by RNA interference suppressed the invasiveness of a pancreatic adenocarcinoma cell line in vitro. These results indicate that TF expression may contribute to the aggressiveness of pancreatic ductal adenocarcinoma by stimulating tumor invasiveness, and that evaluation of the primary tumor for TF expression may identify patients with a poor prognosis.

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The role of RAR and RXR activation in retinoid-induced tissue factor suppression

Cited by 8 publications

References 37 publications

PML/RARα plays a role for basal activity and retinoid-induced repression of the tissue factor promoter in acute promyelocytic leukemia cells

PML/RARα plays a role for basal activity and retinoid-induced repression of the tissue factor promoter in acute promyelocytic leukemia cells

Moderate vitamin A supplementation in obese mice regulates tissue factor and cytokine production in a sex-specific manner

Prognostic Significance of Tissue Factor in Pancreatic Ductal Adenocarcinoma

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