scholarly journals Regulation of HDAC9 Gene Expression by MEF2 Establishes a Negative-Feedback Loop in the Transcriptional Circuitry of Muscle Differentiation

2006 ◽  
Vol 27 (2) ◽  
pp. 518-525 ◽  
Author(s):  
Michael Haberland ◽  
Michael A. Arnold ◽  
John McAnally ◽  
Dillon Phan ◽  
Yuri Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Muscle Development ◽  
Transcriptional Repressor ◽  
Muscle Differentiation ◽  
Negative Feedback Loop ◽  
Bhlh Genes

ABSTRACT Skeletal muscle development is controlled by the myocyte enhancer factor (MEF2) and myogenic basic helix-loop-helix (bHLH) families of transcription factors, which associate and synergistically activate muscle gene expression. Muscle differentiation is further reinforced by positive-feedback loops in which myogenic bHLH proteins activate their own expression and the expression of MEF2, while MEF2 stimulates expression of myogenic bHLH genes and the Mef2c gene. Here we describe a myogenic negative-feedback loop that consists of MEF2 proteins and the transcriptional repressor histone deacetylase 9 (HDAC9). We show that the HDAC9 gene is a direct transcriptional target of MEF2 in vitro and in vivo. HDAC9 can associate with MEF2 proteins and suppress their transcriptional activity. The transcriptional repressor HDAC9 thus forms a negative-feedback loop in the transcriptional circuitry of muscle differentiation.

scholarly journals RAC1/miR-3613/RAC1 feedback loop contributes to ovarian cancer progression

2021 ◽  
Author(s):  
Changzhong Li ◽  
Ruobing Leng ◽  
Yunfang Meng ◽  
Na Li ◽  
Feifei Li ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Progression ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Inhibitory Effect ◽  
Ovarian Cancer Cells ◽  
Negative Feedback Loop

Abstract The RAC1 signal pathway is involved in various tumor cell biological processes. Here, the role of RAC1-miR-3613-RAC1 negative feedback loop in ovarian cancer was explored. Results showed that RAC1 knockdown up-regulated miR-3613, which in turn inhibited RAC1 expression. RAC1 counteracted the inhibitory effect of miR-3613 on the proliferation and invasion of ovarian cancer cells in vitro and on the tumor growth in vivo. In ovarian cancer, miR-3613 expression was negatively correlated with RAC1, and patients with low miR-3613 expression had poor prognosis. These findings indicate the role of RAC1-miR-3613-RAC1 negative feedback loop in the malignant progression of ovarian cancer and its possible therapeutic values.

scholarly journals Long noncoding RNA LINC00518 induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop in melanoma

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Yan Liu ◽  
Dong He ◽  
Mengqing Xiao ◽  
Yuxing Zhu ◽  
Jianda Zhou ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cancer Progression ◽  
Negative Feedback ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Histone Deacetylase 2

AbstractThe long noncoding RNA, LINC00518, is highly expressed in various types of cancers and is involved in cancer progression. Although LINC00518 promotes the metastasis of cutaneous malignant melanoma (CMM), the mechanism underlaying its effects on CMM radiosensitivity remains unclear. In this study, LINC00518 expression was significantly upregulated in CMM samples, and LINC00518 levels were associated with poor prognosis of patients with CMM. Knockdown of LINC00518 in CMM cells significantly inhibited cell invasion, migration, proliferation, and clonogenicity. LINC00518-mediated invasion, migration, proliferation, and clonogenicity were negatively regulated by the microRNA, miR-33a-3p, in vitro, which increased sensitivity to radiotherapy via inhibition of the hypoxia-inducible factor 1α (HIF-1α)/lactate dehydrogenase A glycolysis axis. Additionally, HIF-1α recognized the miR-33a-3p promoter region and recruited histone deacetylase 2, which decreased the expression of miR-33a-3p and formed an LINC00518/miR-33a-3p/HIF-1α negative feedback loop. Furthermore, signaling with initially activated glycolysis and radioresistance in CMM cells was impaired by Santacruzamate A, a histone deacetylase inhibitor, and 2-deoxy-D-glucose, a glycolytic inhibitor. Lastly, knockdown of LINC00518 expression sensitized CMM cancer cells to radiotherapy in an in vivo subcutaneously implanted tumor model. In conclusion, LINC00518 was confirmed to be an oncogene in CMM, which induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop. Our study, may provide a potential strategy to improve the treatment outcome of radiotherapy in CMM.

scholarly journals Long Non-Coding RNA LINC00518 Induces Radioresistance by Regulating Glycolysis Through An miR-33a-3p/HIF-1α Negative Feedback Loop in Melanoma

2020 ◽  
Author(s):  
Ke Cao ◽  
Liu yan ◽  
He Dong ◽  
Xiao Mengqin ◽  
Xiang Liang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Luciferase Reporter ◽  
Negative Feedback Loop ◽  
Reporter System ◽  
Non Coding Rna ◽  
Long Non Coding Rna

Abstract Background: The long non-coding RNA (lncRNA),LINC00518, is highly expressed in many human cancers and is involved in cancer progression. However, the potential function and regulatory mechanism of LINC00518 in cutaneous malignant melanoma (CMM) remain unclear. Methods:Short hairpin RNA (shRNA) was used to silence LINC00518 and HIF-1α, and real-time PCR was performed to determine mRNA expression. Then, cell proliferation, colony formation, flow cytometric, scratch, and transwell assays were to examine the influence of LINC00518 silencing on cellular radiosensitivity. Dual luciferase reporter system,CHIP and COIP was used to verify the target relationship between LINC00518,miR‐33a-5b and HIF-1α,.Glycolysis assays were conducted to exam cell glycolysis process. Western blotting was performed to explore the expression of HIF-1α and LDHA. Finally, animal experiments were performed to demonstrate the effect of LINC00518 silencing on the radiosensitivity of melanoma in vivo.Results: LINC00518 expression was significantly upregulated in CMM samples, and LINC00518 levels were associated with poor prognosis of patients with CMM. Knockdown of LINC00518 in CMM cells significantly inhibited cell invasion, migration, proliferation, and clonogenicity. LINC00518-mediated invasion, migration, proliferation, and clonogenicity were negatively regulated by the microRNA, miR-33a-3p, in vitro, which intensified sensitivity to radiotherapy via inhibition of the hypoxia-induced factor 1α (HIF-1α)/lactate dehydrogenase A (LDHA)-glycolysis axis. Additionally, HIF-1α recognized the miR-33a-3p promoter region and recruited histone deacetylase2 (HDAC2), which decreased the expression of miR-33a-3p and formed an LINC00518/miR-33a-3p/HIF-1α negative feedback loop. Furthermore, signalling initially activated glycolysis and radioresistance in CMM cells was recovered by Santacruzamate A (a histone deacetylase inhibitor) and 2-deoxy-D-glucose (a glycolytic inhibitor). Lastly, knockdown of LINC00518 expression sensitized CMM cancer cells to radiotherapy in an in vivo subcutaneously implanted tumour model. Conclusion: LINC00518 was confirmed to be an oncogene in CMM, which induces radioresistance by regulating glycolysis through an miR-33a-3p/HIF-1α negative feedback loop. Our research may provide a potential strategy to improve the treatment outcome of radiotherapy in CMM.

scholarly journals Twist Regulates Cytokine Gene Expression through a Negative Feedback Loop that Represses NF-κB Activity

Cell ◽  
2003 ◽  
Vol 112 (2) ◽  
pp. 169-180 ◽  
Author(s):  
Dražen Šošić ◽  
James A. Richardson ◽  
Kai Yu ◽  
David M. Ornitz ◽  
Eric N. Olson
Keyword(s):  
Gene Expression ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Cytokine Gene Expression ◽  
Negative Feedback Loop ◽  
Cytokine Gene

scholarly journals Nrg1 Is a Transcriptional Repressor for Glucose Repression of STA1 Gene Expression inSaccharomyces cerevisiae

1999 ◽  
Vol 19 (3) ◽  
pp. 2044-2050 ◽  
Author(s):  
Seok Hee Park ◽  
Sang Seok Koh ◽  
Jae Hwan Chun ◽  
Hye Jin Hwang ◽  
Hyen Sam Kang
Keyword(s):  
Gene Expression ◽  
Zinc Finger Protein ◽  
Glucose Repression ◽  
Transcriptional Repressor ◽  
Dependent Manner ◽  
Expression Of Genes ◽  
Dnase I Footprinting ◽  
Genes Encoding

ABSTRACT Expression of genes encoding starch-degrading enzymes is regulated by glucose repression in the yeast Saccharomyces cerevisiae. We have identified a transcriptional repressor, Nrg1, in a genetic screen designed to reveal negative factors involved in the expression of STA1, which encodes a glucoamylase. TheNRG1 gene encodes a 25-kDa C2H2zinc finger protein which specifically binds to two regions in the upstream activation sequence of the STA1 gene, as judged by gel retardation and DNase I footprinting analyses. Disruption of theNRG1 gene causes a fivefold increase in the level of theSTA1 transcript in the presence of glucose. The expression of NRG1 itself is inhibited in the absence of glucose. DNA-bound LexA-Nrg1 represses transcription of a target gene 10.7-fold in a glucose-dependent manner, and this repression is abolished in bothssn6 and tup1 mutants. Two-hybrid and glutathione S-transferase pull-down experiments show an interaction of Nrg1 with Ssn6 both in vivo and in vitro. These findings indicate that Nrg1 acts as a DNA-binding repressor and mediates glucose repression of the STA1 gene expression by recruiting the Ssn6-Tup1 complex.

scholarly journals Accelerated Response of the myogenin Gene to Denervation in Mutant Mice Lacking Phosphorylation of Myogenin at Threonine 87

2004 ◽  
Vol 24 (5) ◽  
pp. 1983-1989 ◽  
Author(s):  
Chris S. Blagden ◽  
Larry Fromm ◽  
Steven J. Burden
Keyword(s):  
Gene Expression ◽  
Skeletal Muscle ◽  
Electrical Activity ◽  
Muscle Development ◽  
Mutant Mice ◽  
Threonine Residue ◽  
E Boxes ◽  
Bhlh Proteins

ABSTRACT Gene expression in skeletal muscle is regulated by a family of myogenic basic helix-loop-helix (bHLH) proteins. The binding of these bHLH proteins, notably MyoD and myogenin, to E-boxes in their own regulatory regions is blocked by protein kinase C (PKC)-mediated phosphorylation of a single threonine residue in their basic region. Because electrical stimulation increases PKC activity in skeletal muscle, these data have led to an attractive model suggesting that electrical activity suppresses gene expression by stimulating phosphorylation of this critical threonine residue in myogenic bHLH proteins. We show that electrical activity stimulates phosphorylation of myogenin at threonine 87 (T87) in vivo and that calmodulin-dependent kinase II (CaMKII), as well as PKC, catalyzes this reaction in vitro. We find that phosphorylation of myogenin at T87 is dispensable for skeletal muscle development. We show, however, that the decrease in myogenin (myg) expression following innervation is delayed and that the increase in expression following denervation is accelerated in mutant mice lacking phosphorylation of myogenin at T87. These data indicate that two distinct innervation-dependent mechanisms restrain myogenin activity: an inactivation mechanism mediated by phosphorylation of myogenin at T87, and a second, novel regulatory mechanism that regulates myg gene activity independently of T87 phosphorylation.

scholarly journals Defining Akt actions in muscle differentiation

2012 ◽  
Vol 303 (12) ◽  
pp. C1292-C1300 ◽  
Author(s):  
Samantha Gardner ◽  
Magdalena Anguiano ◽  
Peter Rotwein
Keyword(s):  
Growth Factors ◽  
Muscle Development ◽  
Muscle Growth ◽  
Muscle Differentiation ◽  
In Vivo Studies ◽  
Cell Contact ◽  
Muscle Repair ◽  
Complex Signals

Muscle development in childhood and muscle regeneration in adults are highly regulated processes that are necessary for reaching and maintaining optimal muscle mass and strength throughout life. Muscle repair after injury relies on stem cells, termed satellite cells, whose activity is controlled by complex signals mediated by cell-cell contact, by growth factors, and by hormones, which interact with genetic programs controlled by myogenic transcription factors. Insulin-like growth factors (IGFs) play key roles in muscle development and help coordinate muscle repair after injury, primarily by stimulating the phosphatidylinositol 3-kinase-Akt signaling pathway, and both in vitro and in vivo studies have shown that Akt kinase activity is critical for optimal muscle growth and regeneration. Here we find that of the two Akts expressed in muscle, Akt1 is essential for initiation of differentiation in culture and is required for normal myoblast motility, while Akt2 is dispensable. Although Akt2 deficiency did lead to diminished myotube maturation, as assessed by a decline in myofiber area and in fusion index, either Akt1 or Akt2 could restore these processes toward normal. Thus levels of Akt expression rather than distinct actions of individual Akt species are critical for normal myofiber development during the later stages of muscle differentiation.

scholarly journals PIL1 Participates in a Negative Feedback Loop that Regulates Its Own Gene Expression in Response to Shade

2014 ◽  
Vol 7 (10) ◽  
pp. 1582-1585 ◽  
Author(s):  
Lin Li ◽  
Qian Zhang ◽  
Ullas V. Pedmale ◽  
Kazumasa Nito ◽  
Wei Fu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Negative Feedback ◽  
Feedback Loop ◽  
Negative Feedback Loop

scholarly journals Antagonistic Roles of the Tumor Suppressor miR-210-3p and Oncomucin MUC4 Forming a Negative Feedback Loop in Pancreatic Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6197
Author(s):  
Nihad Boukrout ◽  
Mouloud Souidi ◽  
Fatima Lahdaoui ◽  
Belinda Duchêne ◽  
Bernadette Neve ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Chromatin Immunoprecipitation ◽  
Feedback Loop ◽  
Negative Feedback Loop ◽  
Cell Proliferation And Migration ◽  
Muc4 Expression ◽  
And Migration ◽  
Proliferation And Migration

Background: Pancreatic adenocarcinoma (PDAC) is a deadly cancer with an extremely poor prognosis. MUC4 membrane-bound mucin is neoexpressed in early pancreatic neoplastic lesions and is associated with PDAC progression and chemoresistance. In cancers, microRNAs (miRNAs, small noncoding RNAs) are crucial regulators of carcinogenesis, chemotherapy response and even metastatic processes. In this study, we aimed at identifying and characterizing miRNAs activated downstream of MUC4-associated signaling in pancreatic adenocarcinoma. MiRnome analysis comparing MUC4-KD versus Mock cancer cells showed that MUC4 inhibition impaired miR-210-3p expression. Therefore, we aimed to better understand the miR-210-3p biological roles. Methods: miR-210-3p expression level was analyzed by RT-qPCR in PDAC-derived cell lines (PANC89 Mock and MUC4-KD, PANC-1 and MiaPACA-2), as well as in mice and patients tissues. The MUC4-miR-210-3p regulation was investigated using luciferase reporter construct and chromatin immunoprecipitation experiments. Stable cell lines expressing miR-210-3p or anti-miR-210-3p were established using CRISPR/Cas9 technology or lentiviral transduction. We evaluated the biological activity of miR-210-3p in vitro by measuring cell proliferation and migration and in vivo using a model of subcutaneous xenograft. Results: miR-210-3p expression is correlated with MUC4 expression in PDAC-derived cells and human samples, and in pancreatic PanIN lesions of Pdx1-Cre; LstopL-KrasG12D mice. MUC4 enhances miR-210-3p expression levels via alteration of the NF-κB signaling pathway. Chromatin immunoprecipitation experiments showed p50 NF-κB subunit binding on miR-210-3p promoter regions. We established a reciprocal regulation since miR-210-3p repressed MUC4 expression via its 3′-UTR. MiR-210-3p transient transfection of PANC89, PANC-1 and MiaPACA-2 cells led to a decrease in cell proliferation and migration. These biological effects were validated in cells overexpressing or knocked-down for miR-210-3p. Finally, we showed that miR-210-3p inhibits pancreatic tumor growth and proliferation in vivo. Conclusion: We identified a MUC4-miR-210-3p negative feedback loop in early-onset PDAC, but also revealed new functions of miR-210-3p in both in vitro and in vivo proliferation and migration of pancreatic cancer cells, suggesting a complex balance between MUC4 pro-oncogenic roles and miR-210-3p anti-tumoral effects.

scholarly journals Highly Selective Cleavage of TH2-Promoting Cytokines by the Human and the Mouse Mast Cell Tryptases, Indicating a Potent Negative Feedback Loop on TH2 Immunity

2019 ◽  
Vol 20 (20) ◽  
pp. 5147 ◽  
Author(s):  
Zhirong Fu ◽  
Srinivas Akula ◽  
Michael Thorpe ◽  
Lars Hellman
Keyword(s):  
Negative Feedback ◽  
Feedback Loop ◽  
Regulatory Function ◽  
Negative Feedback Loop ◽  
Cytokines And Chemokines ◽  
Th2 Immunity ◽  
Strict Specificity ◽  
Mouse Mast Cell ◽  
Regulatory Functions

Mast cells (MC) are resident tissue cells found primarily at the interphase between tissues and the environment. These evolutionary old cells store large amounts of proteases within cytoplasmic granules, and one of the most abundant of these proteases is tryptase. To look deeper into the question of their in vivo targets, we have analyzed the activity of the human MC tryptase on 69 different human cytokines and chemokines, and the activity of the mouse tryptase (mMCP-6) on 56 mouse cytokines and chemokines. These enzymes were found to be remarkably restrictive in their cleavage of these potential targets. Only five were efficiently cleaved by the human tryptase: TSLP, IL-21, MCP3, MIP-3b, and eotaxin. This strict specificity indicates a regulatory function of these proteases and not primarily as unspecific degrading enzymes. We recently showed that the human MC chymase also had a relatively strict specificity, indicating that both of these proteases have regulatory functions. One of the most interesting regulatory functions may involve controlling excessive TH2-mediated inflammation by cleaving several of the most important TH2-promoting inflammatory cytokines, including IL-18, IL-33, TSLP, IL-15, and IL-21, indicating a potent negative feedback loop on TH2 immunity.

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