Last update 01 Nov 2024

NR2F6

Last update 01 Nov 2024

Basic Info

Synonyms

EAR-2, EAR2, ERBAL2

+ [5]

Introduction

Transcription factor predominantly involved in transcriptional repression. Binds to promoter/enhancer response elements that contain the imperfect 5'-AGGTCA-3' direct or inverted repeats with various spacings which are also recognized by other nuclear hormone receptors. Involved in modulation of hormonal responses. Represses transcriptional activity of the lutropin-choriogonadotropic hormone receptor/LHCGR gene, the renin/REN gene and the oxytocin-neurophysin/OXT gene. Represses the triiodothyronine-dependent and -independent transcriptional activity of the thyroid hormone receptor gene in a cell type-specific manner. The corepressing function towards thyroid hormone receptor beta/THRB involves at least in part the inhibition of THRB binding to triiodothyronine response elements (TREs) by NR2F6. Inhibits NFATC transcription factor DNA binding and subsequently its transcriptional activity. Acts as transcriptional repressor of IL-17 expression in Th-17 differentiated CD4(+) T cells and may be involved in induction and/or maintenance of peripheral immunological tolerance and autoimmunity. Involved in development of forebrain circadian clock; is required early in the development of the locus coeruleus (LC).

Drugs associated with NR2F6

DuraCAR(Regen Biopharma)

Target

NR2F6

Mechanism

NR2F6 inhibitors

Active Org.

Regen Biopharma, Inc.

Originator Org.

Regen Biopharma, Inc.

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

RG-NAE005

Target

NR2F6

Mechanism

NR2F6 agonists

Active Org.

Regen Biopharma, Inc.

Originator Org.

Regen Biopharma, Inc.

Active Indication

Autoimmune Diseases

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

TES-ONC-07

Target

NR2F6

Mechanism

NR2F6 inhibitors

Active Org.

TES Pharma SRL

Originator Org.

TES Pharma SRL

Active Indication

Neoplasms

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with NR2F6

100 Translational Medicine associated with NR2F6

0 Patents (Medical) associated with NR2F6

137

Literatures (Medical) associated with NR2F6

31 Dec 2024·Gut Microbes

Microbial metabolite butyrate modulates granzyme B in tolerogenic IL-10 producing Th1 cells to regulate intestinal inflammation

Article

Author: Khanipov, Kamil ; Yu, Tianming ; Olivares-Villagómez, Danyvid ; Yang, Wenjing ; Golovko, George ; Liu, Xia ; Cong, Yingzi ; Yao, Suxia

CD4⁺ T cells play a critical role in regulating autoimmune diseases, and intestinal microbial metabolites control various immune responses. Granzyme B (GzmB)-producing CD4⁺ T cells have been recently reported to participate in the pathogenesis of autoimmune diseases. Here, we found that GzmbB-deficient CD4⁺ T cells induced more severe colitis in Rag1^-/- mice than wild-type (WT) CD4⁺ T cells. Germ-free (GF) mice exhibited a lower expression of GzmB in intestinal CD4⁺ T cells compared to specific pathogen-free (SPF) mice. Intestinal microbial metabolite butyrate increased GzmB expression in CD4⁺ T cells, especially in IL-10-producing Th1 cells, through HDAC inhibition and GPR43, but not GPR41 and GPR109a. Butyrate-treated GzmB-deficient CD4⁺ T cells demonstrated more severe colitis compared to butyrate-treated WT CD4⁺ T cells in the T cell transfer model. Butyrate altered intestinal microbiota composition, but altered microbiota did not mediate butyrate induction of intestinal CD4⁺ T cell expression of GzmB in mice. Blimp1 was involved in the butyrate induction of GzmB in IL-10-producing Th1 cells. Glucose metabolism, including glycolysis and pyruvate oxidation, mediated butyrate induction of GzmB in Th1 cells. In addition, we found that IKZF3 and NR2F6 regulated GzmB expression induced by butyrate. Together, our studies underscored the critical role of GzmB in mediating gut bacterial metabolite butyrate regulation of T cell tolerance at the mucosal surface.

01 Aug 2024·Journal of Cachexia, Sarcopenia and Muscle

Concerted regulation of skeletal muscle metabolism and contractile properties by the orphan nuclear receptor Nr2f6

Article

Author: de Oliveira, André Gustavo ; Hirabara, Sandro M. ; Silveira, Leonardo R. ; Smith, Jonathon A.B. ; Rizo‐Roca, David ; Araujo, Thiago R. ; da Cruz, Marcos Vinicius ; Barrios, Ninon M. F. ; Vieira, André S. ; Marconato, Emilio ; Jollet, Maxence ; Krook, Anna ; Zierath, Juleen R. ; Guimarães, Dimitrius Santiago P. S. F.

AbstractBackgroundThe maintenance of skeletal muscle plasticity upon changes in the environment, nutrient supply, and exercise depends on regulatory mechanisms that couple structural and metabolic adaptations. The mechanisms that interconnect both processes at the transcriptional level remain underexplored. Nr2f6, a nuclear receptor, regulates metabolism and cell differentiation in peripheral tissues. However, its role in the skeletal muscle is still elusive. Here, we aimed to investigate the effects of Nr2f6 modulation on muscle biology in vivo and in vitro.MethodsGlobal RNA‐seq was performed in Nr2f6 knockdown C2C12 myocytes (N = 4–5). Molecular and metabolic assays and proliferation experiments were performed using stable Nr2f6 knockdown and Nr2f6 overexpression C2C12 cell lines (N = 3–6). Nr2f6 content was evaluated in lipid overload models in vitro and in vivo (N = 3–6). In vivo experiments included Nr2f6 overexpression in mouse tibialis anterior muscle, followed by gene array transcriptomics and molecular assays (N = 4), ex vivo contractility experiments (N = 5), and histological analysis (N = 7). The conservation of Nr2f6 depletion effects was confirmed in primary skeletal muscle cells of humans and mice.ResultsNr2f6 knockdown upregulated genes associated with muscle differentiation, metabolism, and contraction, while cell cycle‐related genes were downregulated. In human skeletal muscle cells, Nr2f6 knockdown significantly increased the expression of myosin heavy chain genes (two‐fold to three‐fold) and siRNA‐mediated depletion of Nr2f6 increased maximal C2C12 myocyte's lipid oxidative capacity by 75% and protected against lipid‐induced cell death. Nr2f6 content decreased by 40% in lipid‐overloaded myotubes and by 50% in the skeletal muscle of mice fed a high‐fat diet. Nr2f6 overexpression in mice resulted in an atrophic and hypoplastic state, characterized by a significant reduction in muscle mass (15%) and myofibre content (18%), followed by an impairment (50%) in force production. These functional phenotypes were accompanied by the establishment of an inflammation‐like molecular signature and a decrease in the expression of genes involved in muscle contractility and oxidative metabolism, which was associated with the repression of the uncoupling protein 3 (20%) and PGC‐1α (30%) promoters activity following Nr2f6 overexpression in vitro. Additionally, Nr2f6 regulated core components of the cell division machinery, effectively decoupling muscle cell proliferation from differentiation.ConclusionsOur findings reveal a novel role for Nr2f6 as a molecular transducer that plays a crucial role in maintaining the balance between skeletal muscle contractile function and oxidative capacity. These results have significant implications for the development of potential therapeutic strategies for metabolic diseases and myopathies.

24 Jun 2024·Nucleic Acids Research

Orphan nuclear receptors-induced ALT-associated PML bodies are targets for ALT inhibition

Article

Author: Boudier, Thomas ; Tzeng, Wan-Yi ; Shen, Yi-Ling ; Tsai, Chia-Tsen ; Joseph, Nithila A ; Chen, Liuh-Yow ; Gaela, Venus Marie ; Hsia, Hsuan-Yu ; Ting, Pin-Chao

AbstractOrphan nuclear receptors (NRs), such as COUP-TF1, COUP-TF2, EAR2, TR2 and TR4, are implicated in telomerase-negative cancers that maintain their telomeres through the alternative lengthening of telomeres (ALT) mechanism. However, how telomere association of orphan NRs is involved in ALT activation remains unclear. Here, we demonstrate that telomeric tethering of orphan NRs in human fibroblasts initiates formation of ALT-associated PML bodies (APBs) and features of ALT activity, including ALT telomere DNA synthesis, telomere sister chromatid exchange, and telomeric C-circle generation, suggesting de novo ALT induction. Overexpression of orphan NRs exacerbates ALT phenotypes in ALT cells, while their depletion limits ALT. Orphan NRs initiate ALT via the zinc finger protein 827, suggesting the involvement of chromatin structure alterations for ALT activation. Furthermore, we found that orphan NRs and deficiency of the ALT suppressor ATRX-DAXX complex operate in concert to promote ALT activation. Moreover, PML depletion by gene knockout or arsenic trioxide treatment inhibited ALT induction in fibroblasts and ALT cancer cells, suggesting that APB formation underlies the orphan NR-induced ALT activation. Importantly, arsenic trioxide administration abolished APB formation and features of ALT activity in ALT cancer cell line-derived mouse xenografts, suggesting its potential for further therapeutic development to treat ALT cancers.

News (Medical) associated with NR2F6

14 Nov 2023

·www.prnewswire.com

Regen BioPharma, Inc. CEO Outlines Future Steps in CAR T Program

SAN DIEGO, Nov. 14, 2023 /PRNewswire/ -- Regen BioPharma, Inc. (OTC PINK: RGBP) (OTC PINK: RGBPP) has previously discussed initiation of its DuraCAR CAR T-cell therapeutic (). This program is designed to create chimeric antigen T-cells that silence the gene for NR2F6. As part of the development of this program, it was discovered that NR2F6 mRNA was greatly increased, thus identifying new, unexpected and potentially extremely useful findings in developing cell therapy treatments for autoimmune disorders . The Company is now preparing a series of in vitro experiments to determine if these DuraCAR cells are indeed immunosuppressive, rather than possessing anti-tumor activity as originally envisioned. "Having had confirmatory studies supporting the increase in NR2F6 gene expression, we now want to see what is happening when these cells are put in a relatively natural environment in the presence of activated immune cells, " says Dr. David Koos, Chairman and CEO of the company. "If these cells do indeed suppress these immune cells, then we will have in hand a potentially extremely valuable approach to suppressing autoimmunity." Future experiments will then be designed to optimize these cells for protecting against major autoimmune disorders such as type 1 diabetes, colitis and arthritis. About Regen BioPharma Inc.: Regen BioPharma, Inc. is a publicly traded biotechnology company (PINK: RGBP) and (PINK: RGBPP). The Company is focused on the immunology and immunotherapy space. The Company is focused on rapidly advancing novel technologies through pre-clinical and Phase I/ II clinical trials. Currently, the Company is focused on mRNA and small molecule therapies for treating cancer and autoimmune disorders. Additional information on Regen BioPharma is available at . Disclaimer: This news announcement may contain forward-looking statements. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. Future events and actual results could differ materially from those set forth in, contemplated by, or underlying the forward-looking statements. The risks and uncertainties to which forward looking statements are subject include, but are not limited to, the effect of government regulation, competition and other material risks. CONTACT INFORMATION: Regen BioPharma Inc. David R. Koos, Ph.D. Chairman & Chief Executive Officer +1-619-722-5505 Phone +1-619-330-2328 Fax Email: [email protected] or [email protected] Twitter (now X): SOURCE Regen BioPharma Inc.

ImmunotherapyCell Therapy

25 Oct 2023

·www.prnewswire.com

Regen BioPharma, Inc. Receives Second Phase Confirmatory Data on its Duracar CAR-T Cell Therapy Program

Autoimmunity to be Targeted SAN DIEGO, Oct. 25, 2023 /PRNewswire/ -- Regen BioPharma, Inc. (OTC PINK: RGBP) (OTC PINK: RGBPP) has previously discussed initiation of a series of experiments to validate its DuraCAR CAR T-cell therapeutic () while also identifying new, unexpected and potentially extremely useful findings in developing cell therapy treatments for autoimmune disorders . The Company has now received the complete set of confirmatory data performed by a second contract research organization (CRO) which is independent of the CRO which performed the initial experiments. These data confirm that T cells which express the chimeric antigen receptor (CAR) construct targeting CD19 and expressing siRNA for NR2F6 had high expression levels of NR2F6 mRNA. NR2F6 is considered an immune checkpoint and thus increasing its activity is likely to lead to immune suppression. "Being able to substantially elevate NR2F6 levels is truly an unexpected, but welcome finding. We now have a sound scientific basis to pursue designing T cells which can tamp down on the uncontrolled immune activation seen in multiple autoimmune disorders," says Dr. Harry Lander, Chief Scientific Consultant to the Company. "We recently filed a patent application around such T cells and we feel we have a head start on this in the scientific community, particularly around using nuclear receptors such as NR2F6." "Having a second confirmatory study gives us confidence we are making the right decision to pursue these novel cell therapies focused on autoimmunity," says Dr. David Koos, Chairman and CEO of the company. "I expect that after consulting with our Board of Advisors and internally, the Company will soon have a clear picture of the specific indications and approaches it will pursue." About Regen BioPharma Inc.: Regen BioPharma, Inc. is a publicly traded biotechnology company (PINK: RGBP) and (PINK: RGBPP). The Company is focused on the immunology and immunotherapy space. The Company is focused on rapidly advancing novel technologies through pre-clinical and Phase I/ II clinical trials. Currently, the Company is focused on mRNA and small molecule therapies for treating cancer and autoimmune disorders. Additional information on Regen BioPharma is available at . Disclaimer: This news announcement may contain forward-looking statements. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. Future events and actual results could differ materially from those set forth in, contemplated by, or underlying the forward-looking statements. The risks and uncertainties to which forward looking statements are subject include, but are not limited to, the effect of government regulation, competition and other material risks. CONTACT INFORMATION: Regen BioPharma Inc. David R. Koos, Ph.D. Chairman & Chief Executive Officer +1-619-722-5505 Phone +1-619-330-2328 Fax Email: [email protected] or [email protected] Twitter (now X): SOURCE Regen BioPharma Inc.

Cell TherapyImmunotherapyPhase 1

18 Oct 2023

·www.prnewswire.com

Regen BioPharma, Inc. Expects Second Phase of Confirmatory Study Shortly

SAN DIEGO, Oct. 18, 2023 /PRNewswire/ -- Regen BioPharma, Inc. (OTC-PINK: RGBP) (OTC-PINK: RGBPP) is currently developing a genetic approach to regulating NR2F6 levels in human T cells. The Company has recently received unexpected and potentially extremely useful data from one of its contract research organizations (CRO) retained to perform experimental studies on the Company's DuraCAR CAR T-cell therapeutic. These studies demonstrated that T cells which express the chimeric antigen receptor (CAR) construct expressing siRNA for NR2F6 can be successfully created. "A second unrelated CRO is currently performing qRT-PCR tests to determine if NR2F6 mRNA is elevated or inhibited by our CAR in T-Cells," says Dr. Harry Lander, Chief Scientific Consultant to the Company." If NR2F6 mRNA is suppressed (stimulating certain immune functions) then this product shows potential for treatment of cancer and if NR2F6 mRNA is elevated (suppressing certain immune functions) then the product shows potential for treatment of autoimmune disorders." Once the Company receives the data, it will analyze the results and report the findings in a press release in order to keep the company's shareholders informed of its progress. "We know our shareholders are anxious to hear about our results surrounding modifying NR2F6 levels in CAR T-cells and we will get this data out as soon as we can," says Dr. David Koos, Chairman and CEO of the company. About Regen BioPharma Inc.: Regen BioPharma, Inc. is a publicly traded biotechnology company (OTC-PINK: RGBP) and (OTC-PINK: RGBPP). The Company is focused on the immunology and immunotherapy space. The Company is focused on rapidly advancing novel technologies through pre-clinical and Phase I/ II clinical trials. Currently, the Company is focused on mRNA and small molecule therapies for treating cancer and autoimmune disorders. Additional information on Regen BioPharma is available at . Disclaimer: This news announcement may contain forward-looking statements. Forward-looking statements are inherently subject to risks and uncertainties, some of which cannot be predicted or quantified. Future events and actual results could differ materially from those set forth in, contemplated by, or underlying the forward-looking statements. The risks and uncertainties to which forward looking statements are subject include, but are not limited to, the effect of government regulation, competition and other material risks. CONTACT INFORMATION: Regen BioPharma Inc. David R. Koos, Ph.D. Chairman & Chief Executive Officer +1-619-722-5505 Phone +1-619-330-2328 Fax Email: [email protected] SOURCE Regen BioPharma, Inc.

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NR2F6

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