Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis

Das, Jayanta; Felty, Quentin; Poppiti, Robert; Jackson, Robert M.; Roy, Deodutta

doi:10.3390/cells7120234

Cited by 34 publications

(17 citation statements)

References 40 publications

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“…Besides its role in the regulation of mitochondrial functions, NRF1 is also a crucial player in histone gene expression and acts as a regulator of cell growth and proliferation [ 13 , 14 ]. Accumulating evidences also implicate that NRF1 expression and its transcription factor activity may contribute to the pathogenesis of breast cancer, glioblastoma, and neuronal dysfunction [ 15 , 16 , 17 ].…”

Section: Introductionmentioning

confidence: 99%

Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor

Rajasekaran

Song

Lee

et al. 2021

IJMS

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SMAD4, a key regulator of transforming growth factor-β (TGF-β) signaling, plays a major role in cell growth, migration, and apoptosis. In particular, TGF-β/SMAD induces growth arrest, and SMAD4 induces the expression of target genes such as p21WAF1 and p15INK4b through its interaction with several cofactors. Thus, inactivating mutations or the homozygous deletion of SMAD4 could be related to tumorigenesis or malignancy progression. However, in some cancer types, SMAD4 is neither mutated nor deleted. In the current study, we demonstrate that TGF-β signaling with a preserved SMAD4 function can contribute to cancer through associations with negative pathway regulators. We found that nuclear respiratory factor-1 (NRF1) is a novel interaction SMAD4 partner that inhibits TGF-β/SMAD4-induced p15INK4b mRNA expression by binding to SMAD4. Furthermore, we confirmed that NRF1 directly binds to the core region of the SMAD4 promoter, thereby decreasing SMAD4 mRNA expression. On the whole, our data suggest that NRF1 is a negative regulator of SMAD4 and can interfere with TGF-β/SMAD-induced tumor suppression. Our findings provide a novel perception into the molecular basis of TGF-β/SMAD4-signaling suppression in tumorigenesis.

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Section: Introductionmentioning

confidence: 99%

Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor

Rajasekaran

Song

Lee

et al. 2021

IJMS

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“…Our transcriptome analysis revealed substantial changes in CD62L, JAK2, PIM-1, GRK6, HIF-1α, YY-1, NRF-1, and CREB-1 gene expression. These genes have all independently been reported to regulate mRNA transcription, lymphocyte expression, and signaling function of CXCR4 [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. Specifically, our data show an increase in PIM-1 (negative transcriptional regulator) and a decrease in NRF-1 and HIF-1α (positive transcriptional regulators) after ex vivo expansion.…”

Section: Discussionmentioning

confidence: 99%

RNA-Seq Analysis Reveals CCR5 as a Key Target for CRISPR Gene Editing to Regulate In Vivo NK Cell Trafficking

Levy

Clara

Reger

et al. 2021

Cancers

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A growing number of natural killer (NK) cell-based immunotherapy trials utilize ex vivo expansion to grow and activate allogenic and autologous NK cells prior to administration to patients with malignancies. Recent data in both murine and macaque models have shown that adoptively infused ex vivo expanded NK cells have extensive trafficking into liver tissue, with relatively low levels of homing to other sites where tumors often reside, such as the bone marrow or lymph nodes. Here, we evaluated gene and surface expression of molecules involved in cellular chemotaxis in freshly isolated human NK cells compared with NK cells expanded ex vivo using two different feeder cells lines: Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCLs) or K562 cells with membrane-bound (mb) 4-1BB ligand and interleukin (IL)-21. Expanded NK cells had altered expression in a number of genes that encode chemotactic ligands and chemotactic receptors that impact chemoattraction and chemotaxis. Most notably, we observed drastic downregulation of C-X-C chemokine receptor type 4 (CXCR4) and upregulation of C-C chemokine receptor type 5 (CCR5) transcription and phenotypic expression. clustered regularly interspaced short palindromic repeats (CRISPR) gene editing of CCR5 in expanded NK cells reduced cell trafficking into liver tissue and increased NK cell presence in the circulation following infusion into immunodeficient mice. The findings reported here show that ex vivo expansion alters multiple factors that govern NK cell homing and define a novel approach using CRISPR gene editing that reduces sequestration of NK cells by the liver.

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“…Our results showed that ERβ expression was significantly increased in endometriotic cells as well as ERβ target genes, including SOD2, NRF1, COX2, and MMP1, subsequently contributing to endometriosis (EMS) development ( 4 , 5 ), while ERα expression was significantly decreased, and the ERβ:ERα ratio in endometriotic 12Z cells is increased to 38:1 compared to endometrial HEEC cells as calculated from data in Figure 1A , which is consistent with previous report ( 4 , 5 ). In addition, increased SOD2 expression results in decreased reactive oxygen species (ROS) formation and minimized oxidative stress and increases the invasiveness of cell growth ( 37 ), while increased NRF1 expression triggers mitochondrial replication through Tfam (transcription factor A, mitochondrial) ( 7 , 38 ), providing stronger respiration and metabolic energy for cell proliferation ( 39 ). On the other hand, increased COX2 expression involves with inflammation and COX2-derived prostaglandin E2 (PGE2) biosynthesis contributes to EMS-related pain and infertility ( 1 , 13 ), while increased MMP1 expression is involved with tissue degradation, menstrual bleeding, and invasion of seeded endometriotic explants ( 14 , 15 ).…”

Section: Discussionmentioning

confidence: 99%

Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway

et al. 2020

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Endometriosis is an inflammatory gynecological disorder characterized by endometrial tissue growth located outside of the uterine cavity in addition to chronic pelvic pain and infertility. In this study, we aim to develop a potential therapeutic treatment based on the pathogenesis and mechanism of Endometriosis. Our preliminary data showed that the expression of estrogen receptor β (ERβ) was significantly increased, while ERα was significantly decreased, in endometriotic cells compared to normal endometrial cells. Further investigation showed that betulinic acid (BA) treatment suppressed ERβ expression through epigenetic modification on the ERβ promoter, while had no effect on ERα expression. In addition, BA treatment suppresses ERβ target genes, including superoxide dismutase 2 (SOD2), nuclear respiratory factor-1 (NRF1), cyclooxygenase 2 (COX2), and matrix metalloproteinase-1 (MMP1), subsequently increasing oxidative stress, triggering mitochondrial dysfunction, decreasing elevated proinflammatory cytokines, and eventually suppressing endometriotic cell proliferation, mimicking the effect of ERβ knockdown. On the other hand, gain of ERβ by lentivirus infection in normal endometrial cells resulted in increased cell proliferation and proinflammatory cytokine release, while BA treatment diminished this effect through ERβ suppression with subsequent oxidative stress and apoptosis. Our results indicate that ERβ may be a major driving force for the development of endometriosis, while BA inhibits Endometriosis through specific suppression of the ERβ signaling pathway. This study provides a novel therapeutic strategy for endometriosis treatment through BA-mediated ERβ suppression.

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Nuclear Respiratory Factor 1 Acting as an Oncoprotein Drives Estrogen-Induced Breast Carcinogenesis

Cited by 34 publications

References 40 publications

Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor

Nuclear Respiratory Factor-1, a Novel SMAD4 Binding Protein, Represses TGF-β/SMAD4 Signaling by Functioning as a Transcriptional Cofactor

RNA-Seq Analysis Reveals CCR5 as a Key Target for CRISPR Gene Editing to Regulate In Vivo NK Cell Trafficking

Betulinic Acid Inhibits Endometriosis Through Suppression of Estrogen Receptor β Signaling Pathway

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