NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism

Pei, Liming; Waki, Hironori; Vaitheesvaran, Bhavapriya; Wilpitz, Damien C.; Kurland, Irwin J.; Tontonoz, Peter

doi:10.1038/nm1471

Cited by 287 publications

(272 citation statements)

References 48 publications

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“…NR4A2 has also been tested as a candidate tumor suppressor gene where siRNA knock-down in HeLa cells was associated with parameters of growth inhibition and apoptosis (Ke et al, 2004). In addition, deregulation of NR4A1-3 family members have been associated with both alterations in glucose metabolism (Pei et al, 2006), as well as cell survival signals (Wallen-Mackenzie et al, 2003) and tumorigenesis . The low or undetectable levels of steady-state NR4A2 expression observed in LKB1 wild-type lung tumor cell lines when grown to confluence is also consistent with previous data from studies on colon cancer cell lines which showed low or undetectable NR4A2 expression under basal growth conditions, but induction of NR4A2 following incubation with the prostaglandin PGE2 (Holla et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

et al. 2009

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Activation of Crtc1 (also known as Mect1/Torc1) by a t(11;19) chromosomal rearrangement underlies the etiology of malignant salivary gland tumors. As LKB1 is a target for mutational inactivation in lung cancer and was recently shown to regulate hepatic Crtc2/CREB transcriptional activity in mice, we now present evidence suggesting disruption of an LKB1/Crtc pathway in cancer. Although Crtc1 is preferentially expressed in adult brain tissues, we observed elevated levels of steadystate Crtc1 in thoracic tumors. In addition, we show that somatic loss of LKB1 is associated with underphosphorylation of endogenous Crtc1, enhanced Crtc1 nuclear localization and enhanced expression of the Crtc prototypic target gene, NR4A2/Nurr1. Inhibition of NR4A2 was associated with growth suppression of LKB1 null tumors, but showed little effect on LKB1-wildtype cells. These data strengthen the role of dysregulated Crtc as a bona fide cancer gene, present a new element to the complex LKB1 tumorigenic axis, and suggest that Crtc genes may be aberrantly activated in a wider range of common adult malignancies.

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Section: Discussionmentioning

confidence: 99%

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

et al. 2009

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“…11,12 This has led to direct speculation by others that these factors may contribute significantly to the transcriptional regulation of this process, although their importance was not experimentally tested in these studies. The recent demonstration that Nur77 regulates lipolysis in skeletal muscle cells 13 and hepatic gluconeogenesis, 14 highlights its potential importance in energy metabolism. The metabolic role of Nur77 in other tissues and the direct speculation by others that NR4A factors might play a key role, led us to investigate their role in adipogenesis.…”

Section: Introductionmentioning

confidence: 99%

The NR4A family of orphan nuclear receptors are not required for adipogenesis

O’Rahilly

et al. 2007

Int J Obes

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Nuclear hormone receptors of the NR4A subfamily are rapidly induced during the early stages of adipogenesis, leading to the speculation that they may have important roles in this process. One of the three subfamily members, Nur77 has also been shown to play key roles in energy expenditure and lipolysis in skeletal muscle and in the control of hepatic gluconeogenesis. We, therefore, examined the role of NR4A factors in adipogenesis using the well-characterized 3T3-L1 preadipocyte model. Inhibition of Nur77 expression using siRNA did not affect induction of adipogenic genes, nor the accumulation of lipid. To inhibit the activity of all the three NR4A family members, we generated preadipocytes stably expressing a well-characterized dominant-negative Nur77 (DN-Nur77), known to block the function of the other NR4A factors, Nurr1 and Nor1, as well as Nur77. While the increased NR4A activity observed following adipogenic induction was completely abolished in these cells, DNNur77 expression did not affect the expression of genes characteristic of terminally differentiated adipocytes and had no impact on lipid accumulation in these cells. Thus, while members of the NR4A subfamily of nuclear receptors may have important metabolic roles in skeletal muscle and liver, we demonstrate that they are dispensable for normal adipocyte development.

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“…The nuclear orphan receptors are known to be immediate early response genes induced by a wide range of extracellular signals, including growth factors, apoptotic and inflammatory signals, and hormones, in a cell type-specific manner. 7,8 To our knowledge to date, Nurr1 has mainly been studied as a transcription factor in the nucleus. Mutations in the coding gene have been associated with neurologic diseases, including Parkinson disease, schizophrenia, and manic depression.…”

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confidence: 99%

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

Inamoto

Czerniak

Dinney

et al. 2009

Cancer

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BACKGROUND:Nurr1 belongs to a novel class of orphan nuclear receptors (the NR4A family). The authors have previously shown that Nurr1 is important in carcinogenesis. In the current study, they examined the clinicopathologic relevance of expression patterns of Nurr1 in bladder tumors.METHODS:Nurr1 expression was determined using immunohistochemical staining in a bladder cancer tissue array (145 tumors). Tumors were classified according to Nurr1 protein levels in both cytoplasm and nucleus. Disease‐specific survival and recurrence‐free survival were investigated by Kaplan‐Meier analysis and Cox proportional hazards analysis in multivariate models and correlated with variables such as tumor stage, growth pattern, and clinical outcome (recurrence and survival). In vitro, Nurr1 was examined for its role in bladder cancer cell proliferation and migration using small interfering RNA silencing.RESULTS:Nurr1 expression in tumor cells correlated with increasing tumor stage and invasive growth pattern. Disease‐specific survival was significantly shorter in patients whose tumors demonstrated a high level of cytoplasmic Nurr1 compared with those with lower levels of cytoplasmic Nurr1 expression. Furthermore, cytoplasmic Nurr1 expression level was found to be an independent predictor of disease‐specific survival (odds ratio, 4.894; P < .001). In vitro, silencing of endogenous Nurr1 attenuated the migration of bladder cancer cells.CONCLUSIONS:The expression of Nurr1 in the cytoplasm correlates with adverse outcome and is an independent prognostic marker for tumor progression and survival in patients with bladder cancer. This might represent a novel target in bladder cancer therapy. Cancer 2010. © 2010 American Cancer Society.

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NR4A orphan nuclear receptors are transcriptional regulators of hepatic glucose metabolism

Cited by 287 publications

References 48 publications

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

Enhanced activity of the CREB co-activator Crtc1 in LKB1 null lung cancer

The NR4A family of orphan nuclear receptors are not required for adipogenesis

Cytoplasmic mislocalization of the orphan nuclear receptor Nurr1 is a prognostic factor in bladder cancer

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