Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells

Gizard, Florence; Zhao, Yue; Findeisen, Hannes M.; Qing, Hua; Cohn, Dianne; Heywood, Elizabeth B.; Jones, Karrie L.; Nomiyama, Takashi; Bruemmer, Dennis

doi:10.1074/jbc.m111.295840

Cited by 26 publications

(20 citation statements)

References 30 publications

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“…A Skp2 adenoviral (Ad) expression construct 30 was titrated in order to maintain expression while minimizing potential off-target effects (data not shown). A titer of ~2000vp/cell resulted in robust expression of Skp2 as compared to GFP control, but had minimal effect on endogenous p27 kip1 levels (Fig.…”

Section: Resultsmentioning

confidence: 99%

A Receptor-Specific Function for Notch2 in Mediating Vascular Smooth Muscle Cell Growth Arrest Through Cyclin-dependent Kinase Inhibitor 1B

Boucher

Harrington

Rostama

et al. 2013

Circulation Research

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Rationale Deregulated vascular smooth muscle cell (VSMC) proliferation contributes to multiple vascular pathologies, and Notch signaling regulates VSMC phenotype. Objective Previous work focused on Notch1 and Notch3 in VSMC during vascular disease; however, the role of Notch2 is unknown. Because injured murine carotid arteries display increased Notch2 in VSMC as compared to uninjured arteries, we sought to understand the impact of Notch2 signaling in VSMC. Methods and Results In human primary VSMC, Jagged-1 (Jag-1) significantly reduced proliferation through specific activation of Notch2. Increased levels of p27kip1 were observed downstream of Jag-1/Notch2 signaling, and required for cell cycle exit. Jag-1 activation of Notch resulted in increased phosphorylation on serine 10, decreased ubiquitination and prolonged half-life of p27kip1. Jag-1/Notch2 signaling robustly decreased S-phase kinase associated protein (Skp2), an F-box protein that degrades p27kip1 during G1. Over expression of Skp2 prior to Notch activation by Jag-1 suppressed the induction of p27kip1. Additionally, increased Notch2 and p27kip1 expression was co-localized to the non-proliferative zone of injured arteries as indicated by co-staining with proliferating cell nuclear antigen (PCNA), whereas Notch3 was expressed throughout normal and injured arteries, suggesting Notch2 may negatively regulate lesion formation. Conclusions We propose a receptor specific function for Notch2 in regulating Jag-1-induced p27kip1 expression and growth arrest in VSMC. During vascular remodeling, co-localization of Notch2 and p27kip1 to the non-proliferating region supports a model where Notch2 activation may negatively regulate VSMC proliferation to lessen the severity of the lesion. Thus Notch2 is a potential target for control of VSMC hyperplasia.

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Section: Resultsmentioning

confidence: 99%

A Receptor-Specific Function for Notch2 in Mediating Vascular Smooth Muscle Cell Growth Arrest Through Cyclin-dependent Kinase Inhibitor 1B

Boucher

Harrington

Rostama

et al. 2013

Circulation Research

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“…HEK 293 cells were transiently transfected with a NOR1 or green fluorescent protein expression vector using Lipofectamine 2000 (Invitrogen, Grand Island, NY, http://www.lifetechnologies.com/) as described . RNA was collected with Trizol (Invitrogen, Grand Island, NY, http://www.lifetechnologies.com/) 48 hours after transfection.…”

Section: Methodsmentioning

confidence: 99%

Deficiency of the NR4A Orphan Nuclear Receptor NOR1 in Hematopoietic Stem Cells Accelerates Atherosclerosis

et al. 2014

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Objective The NR4A orphan nuclear receptor NOR1 functions as a constitutively active transcription factor regulating cellular inflammation and proliferation. In the present study, we employed bone marrow transplantation to determine the selective contribution of NOR1 expression in hematopoietic stem cells to the development of atherosclerosis. Methods and Results Reconstitution of lethally irradiated apoE−/− mice with NOR1-deficient hematopoietic stem cells accelerated atherosclerosis formation and macrophage recruitment following feeding a diet enriched in saturated fat. NOR1 deficiency in hematopoietic stem cells induced splenomegaly and monocytosis, specifically the abundance of inflammatory Ly6C+ monocytes. Bone marrow transplantation studies further confirmed that NOR1 suppresses the proliferation of macrophage and dendritic progenitor (MDP) cells. Expression analysis identified RUNX1, a critical regulator of hematopoietic stem cell expansion, as a target gene suppressed by NOR1 in MDP cells. Finally, in addition to inducing Ly6C+ monocytosis, NOR1 deletion increased the replicative rate of lesional macrophages and induced local foam cell formation within the atherosclerotic plaque. Conclusion Collectively, our studies demonstrate that NOR1 deletion in hematopoietic stem cells accelerates atherosclerosis formation by promoting myelopoiesis in the stem cell compartment and by inducing local pro-atherogenic activities in the macrophage, including lesional macrophage proliferation and foam cell formation.

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“…NR4A3-induced proliferation has been linked to regulation of cyclins D1 and D2 [174, 175] and S-phase kinase-associated protein 2 (Skp2) which results in decreased expression of the cyclin-dependent kinase inhibitor p27 [176]. A recent study showed that miR-638 is also a key regulator of smooth muscle cell proliferation by targeting NR4A3 which results in silencing of NR4A3-regulated genes involved in cell proliferation [177].…”

Section: Nr4a3 In Cellular Homeostasis and Diseasementioning

confidence: 99%

Nuclear receptor 4A (NR4A) family – orphans no more

Safe

Jin

Morpurgo

et al. 2016

The Journal of Steroid Biochemistry and Molecular Biology

151

161

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The orphan nuclear receptors NR4A1, NR4A2 and NR4A3 are immediate early genes induced by multiple stressors, and the NR4A1 receptors play an important role in maintaining cellular homeostasis and disease. There is increasing evidence for the role of these receptors in metabolic, cardiovascular and neurological functions and also in inflammation and inflammatory diseases and in immune functions and cancer. Despite the similarities of NR4A1, NR4A2 and NR4A3 and their interactions with common cis-genomic elements, they exhibit unique activities and cell-/tissue-specific functions. Although endogenous ligands for NR4A receptors have not been identified, there is increasing evidence that structurally-diverse synthetic molecules can directly interact with the ligand binding domain of NR4A1 and act as agonists or antagonists, and ligands for NR4A2 and NR4A3 have also been identified. Since NR4A receptors are key factors in multiple diseases, there are opportunities for the future development of NR4A ligands for clinical applications in treating multiple health problems including metabolic, neurologic and cardiovascular diseases, other inflammatory conditions, and cancer.

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Transcriptional Regulation of S Phase Kinase-associated Protein 2 by NR4A Orphan Nuclear Receptor NOR1 in Vascular Smooth Muscle Cells

Cited by 26 publications

References 30 publications

A Receptor-Specific Function for Notch2 in Mediating Vascular Smooth Muscle Cell Growth Arrest Through Cyclin-dependent Kinase Inhibitor 1B

A Receptor-Specific Function for Notch2 in Mediating Vascular Smooth Muscle Cell Growth Arrest Through Cyclin-dependent Kinase Inhibitor 1B

Deficiency of the NR4A Orphan Nuclear Receptor NOR1 in Hematopoietic Stem Cells Accelerates Atherosclerosis

Nuclear receptor 4A (NR4A) family – orphans no more

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