Abstract:Nor-1 belongs to the nur subfamily of nuclear receptor transcription factors. The precise role of Nor-1 in mammalian development has not been established. However, recent studies indicate a function for this transcription factor in oncogenesis and apoptosis. To examine the spatiotemporal expression pattern of Nor-1 and the developmental and physiological consequences of Nor-1 ablation, Nor-1-null mice were generated by insertion of the lacZ gene into the Nor-1 genomic locus. Disruption of the Nor-1 gene result… Show more
“…Transgenic expression of a dominant negative Nur77 protein, which can inhibit both Nur77 and Nor-1, does antagonize negative selection. 75,76 Therefore, it has been hypothesized that there may be redundancies between the family members. How Nur77 can induce apoptosis is still unclear, but one proposed mechanism is that upon TCR stimulation Nur77 is translocated from the nucleus to the mitochondria where it interacts with BCL-2 inducing a conformational change that converts BCL-2 into a proapoptotic molecule.…”
Apoptosis is a conserved genetic program critical for the development and homeostasis of the immune system. During the early stages of lymphopoiesis, growth factor signaling is an essential regulator of homeostasis by regulating the survival of lymphocyte progenitors. During differentiation, apoptosis ensures that lymphocytes express functional antigen receptors and is essential for eliminating lymphocytes with dangerous self-reactive specificities. Many of these critical cell death checkpoints during immune development are regulated by the BCL-2 family of proteins, which is comprised of both pro-and antiapoptotic members, and members of the tumor necrosis factor death receptor family. Aberrations in the expression or function of these cell death modulators can result in pathological conditions including immune deficiency, autoimmunity, and cancer. This review will describe how apoptosis regulates these critical control points during immune development.
“…Transgenic expression of a dominant negative Nur77 protein, which can inhibit both Nur77 and Nor-1, does antagonize negative selection. 75,76 Therefore, it has been hypothesized that there may be redundancies between the family members. How Nur77 can induce apoptosis is still unclear, but one proposed mechanism is that upon TCR stimulation Nur77 is translocated from the nucleus to the mitochondria where it interacts with BCL-2 inducing a conformational change that converts BCL-2 into a proapoptotic molecule.…”
Apoptosis is a conserved genetic program critical for the development and homeostasis of the immune system. During the early stages of lymphopoiesis, growth factor signaling is an essential regulator of homeostasis by regulating the survival of lymphocyte progenitors. During differentiation, apoptosis ensures that lymphocytes express functional antigen receptors and is essential for eliminating lymphocytes with dangerous self-reactive specificities. Many of these critical cell death checkpoints during immune development are regulated by the BCL-2 family of proteins, which is comprised of both pro-and antiapoptotic members, and members of the tumor necrosis factor death receptor family. Aberrations in the expression or function of these cell death modulators can result in pathological conditions including immune deficiency, autoimmunity, and cancer. This review will describe how apoptosis regulates these critical control points during immune development.
“…Cell proliferation is initially widespread in the prospective canal region, but after canal formation it becomes restricted to two regions of the canal ( Fig. 2.7; Chang et al 1999;Ponnio et al 2002). The loss of Nor-1 affected the proliferation and continual growth of all three canals and ampullae.…”
Section: Development Of the Semicircular Canalsmentioning
confidence: 99%
“…Although the expression patterns of Netrin 1 and Nor-1 in the inner ear are similar (highest in the fusion plate region), loss of Nor-1 function does not affect canal resorption. In Nor-1 knockout mice, the canals and ampullae are smaller than in wildtype mice (Ponnio et al 2002). Cell proliferation is initially widespread in the prospective canal region, but after canal formation it becomes restricted to two regions of the canal ( Fig.…”
Section: Development Of the Semicircular Canalsmentioning
“…NOR1 is highly expressed in the central nervous system during embryonic development (21). Our studies using previously generated NOR1-deficient mice demonstrated that NOR1 plays a critical role in neuronal survival, axonal guidance, and is required for the continuous proliferative growth of the semicircular canals (22,23). In addition, experiments using overexpression of NOR1 revealed that constitutive NOR1 expression in thymocytes results in apoptosis (24).…”
Members of the nuclear hormone receptor superfamily function as key transcriptional regulators of inflammation and proliferation in cardiovascular diseases. In addition to the ligand-dependent peroxisome proliferator-activated receptors and liver X receptors, this family of transcription factors includes a large number of orphan receptors, and their role in vascular diseases remains to be investigated. The neuron-derived orphan receptor-1 (NOR1) belongs to the ligand-independent NR4A subfamily, which has been implicated in cell proliferation, differentiation, and apoptosis. In this study, we demonstrate NOR1 expression in vascular smooth muscle cells (SMC) of human atherosclerotic lesions. In response to mitogenic stimulation with platelet-derived growth factor (PDGF), SMC rapidly express NOR1 through an ERK-MAPK-dependent signaling pathway. 5-Deletion analysis, site-directed mutagenesis, and transactivation experiments demonstrate that PDGF-induced NOR1 expression is mediated through a cAMPresponse element-binding protein (CREB)-dependent transactivation of the NOR1 promoter. Consequently, short interfering RNAmediated depletion of CREB abolished PDGF-induced NOR1 expression in SMC. Furthermore, PDGF induced Ser-133 phosphorylation of CREB and subsequent binding to the CRE sites of the endogenous NOR1 promoter. Functional analysis demonstrated that PDGF induces NOR1 transactivation of its consensus NGFI-B-response elements (NBRE) in SMC. We finally demonstrate that SMC isolated from NOR1-deficient mice exhibit decreased cell proliferation and characterize cyclin D1 and D2 as NOR1 target genes in SMC. These experiments indicate that PDGF-induced NOR1 transcription in SMC is mediated through CREB-dependent transactivation of the NOR1 promoter and further demonstrate that NOR1 functions as a key transcriptional regulator of SMC proliferation.Atherosclerosis, the subsequent development of occlusive vascular diseases, and the failure of treatment approaches such as postangioplasty restenosis involve several interrelated processes (1, 2). In addition to endothelial dysfunction and inflammation, proliferation of smooth muscle cells (SMC) 3 is considered to play a pivotal role in the pathogenesis of atherosclerosis and the failure of interventional approaches used to treat related occlusive vascular complications (2-4). With the evolving understanding of the mechanisms contributing to the development of vascular diseases, members of the nuclear hormone receptor superfamily of transcription factors have emerged as key transcriptional regulators of inflammation and cell proliferation (5, 6). Based on this evidence, elucidation of the molecular pathways utilized by nuclear receptors to regulate programs of gene expression is expected to facilitate the development of novel pharmacological approaches for the treatment of cardiovascular diseases. Nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) and liver X receptor (LXR) subfamilies are expressed in SMC and inhibit their proliferation in response ...
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