Cell growth/survival As a steroid/thyroid hormone receptor, NR4A1 acts as a transcription factor, activating several genes involved in cell growth and survival (Bras et al., 2000). The expression of NR4A1 can be induced by tumor necrosis factor, growth factor, nerve growth factor and T-cell receptor-mediated signaling, implying a role of NR4A1 in cell proliferation (Bras et al., 2000). In addition, nerve growth factor IB and nuclear receptor subfamily 4 response elements, suggesting that NR4A1 functions in growth and cell cycle control (Pei et al., 2006). A dominant negative mutation in the transactivation domain of NR4A1 reduces cultured mouse embryonic cell growth in a tumor necrosis factor-dependent manner (Suzuki et al., 2003). Silencing of NR4A1 by siRNA treatment causes a dramatic reduction in growth/survival of HeLa, DLD1, HCT116, PC3, U87, and AsPC1 cell lines (Ke et al., 2004). Thus, NR4A1 appear to be involved in cell growth and survival, but the detailed mechanisms are still largely unknown.
Apoptosis Contradictory to its apparent role in cell survival, NR4A1 also activates several genes involved in cell apoptosis as well as translocating directly into mitochondria to enhance the apoptotic signal (Li et al., 2000; Lin et al., 2004; Zhang et al., 1999). For example, NR4A1 induces apoptosis in cultured prostate cancer cells through activation of the transcription factor E2F1 (Mu and Chang, 2003; Wilson et al., 2003). NR4A1 also mediates apoptosis through translocation from the nucleus into mitochondria where it interacted with the apoptosis regulating protein Bcl-2 to release cytochrome c (Lin et al., 2004; Suzuki et al., 2003). Another apoptosis regulating protein, BAX, is thought to recruit NR4A1 into the mitochondria to mediate apoptosis (Wilson et al., 2003). NR4A1 further induces apoptosis by reacting with self-recognizing major histocompatibility complex molecules in T cell (Zhang et al., 1999). NR4A1 acts as an inflammatory factor in T-cell, and T-cell receptor-mediated apoptosis can be prevented by inhibiting NR4A1 function (Liu et al., 1994; Woronicz et al., 1994). Thus, it appears that NR4A1 plays different and opposing roles in cell survival and apoptosis depending on the cell status and molecular environment (Mohan et al., 2012).
Neuronal regulation GFP-tagged NR4A1 is associated with dopamine receptor D1 positive neurons in brain tissue of transgenic mice (Davis and Puhl, 2011). NR4A1 activity closely correlates with dopamine neurotransmission in the central nervous system of mice (Gilbert et al., 2006). Furthermore, NR4A1 induces immediate early genes within central nervous system cells and basal ganglia of adult mice (Heiman et al., 2008; Lobo et al., 2006). NR4A1 deficient mice exhibit dysfunctional locomotor behavior due to alteration of dopamine neuron activity (Gilbert et al., 2006). Although NR4A1 is clearly involved in dopamine neuron activity, the specific mechanisms of this involvement remain unknown (Perlmann and Wallen-Mackenzie, 2004).
Muscle homeostasis and metabolism In skeletal muscle, NR4A1 expression is enhanced by activation of the beta-adrenergic signaling pathway during muscle hypertrophy and endurance exercise (Mahoney et al., 2005; Maxwell et al., 2005; Pearen et al., 2006). Knockdown of NR4A1 by siRNA treatment causes repression of several genes associated with lipid, carbohydrate and glucose metabolism including the genes for AMP-activated protein kinase subunit gamma 3, fatty acid translocase and glucose transporter 4 (Maxwell et al., 2005; Chao et al., 2007). Interestingly, NR4A1 appears to influence energy balance and thermogenesis control through uncoupling of mitochondrial respiration (Kanzleiter et al., 2005). These findings suggest that NR4A1 is involved in energy metabolism and muscle energetics and function.
NCBI: 3164 MIM: 139139 HGNC: 7980 Ensembl: ENSG00000123358
dbSNP: 3164 ClinVar: 3164 TCGA: ENSG00000123358 COSMIC: NR4A1
Tzu-Min Chan ; Shinn-Zong Lin ; Tzyy-Wen Chiou ; Horng-Jyh Harn
NR4A1 (nuclear receptor subfamily 4, group A, member 1)
Atlas Genet Cytogenet Oncol Haematol. 2013-01-01
Online version: http://atlasgeneticsoncology.org/gene/41573/deep-insight-explorer/css/cancer-prone-explorer/