Functional Role of AKNA: A Scoping Review

Human akna encodes an AT-hook transcription factor whose expression participates in various cellular processes. We conducted a scoping review on the literature regarding the functional role of AKNA according to the evidence found in human and in vivo and in vitro models, stringently following the “PRISMA-ScR” statement recommendations. Methods: We undertook an independent PubMed literature search using the following search terms, AKNA OR AKNA ADJ gene OR AKNA protein, human OR AKNA ADJ functions. Observational and experimental articles were considered. The selected studies were categorized using a pre-determined data extraction form. A narrative summary of the evidence was produced. Results: AKNA modulates the expression of CD40 and CD40L genes in immune system cells. It is a negative regulator of inflammatory processes as evidenced by knockout mouse models and observational studies for several autoimmune and inflammatory diseases. Furthermore, AKNA contributes to the de-regulation of the immune system in cancer, and it has been proposed as a susceptibility genetic factor and biomarker in CC, GC, and HNSCC. Finally, AKNA regulates neurogenesis by destabilizing the microtubules dynamics. Conclusion: Our results provide evidence for the role of AKNA in various cellular processes, including immune response, inflammation, development, cancer, autoimmunity, and neurogenesis.

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WNT-5A regulates TGF-β-related activities in liver fibrosis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00160.2016 ◽

2017 ◽

Vol 312 (3) ◽

pp. G219-G227 ◽

Cited By ~ 21

Author(s):

Leonie Beljaars ◽

Sara Daliri ◽

Christa Dijkhuizen ◽

Klaas Poelstra ◽

Reinoud Gosens

Keyword(s):

Liver Fibrosis ◽

Functional Role ◽

Collagen Type ◽

Collagen Type I ◽

Matrix Proteins ◽

Type I ◽

Human Livers

WNT-5A is a secreted growth factor that belongs to the noncanonical members of the Wingless-related MMTV-integration family. Previous studies pointed to a connection between WNT-5A and the fibrogenic factor TGF-β warranting further studies into the functional role of WNT-5A in liver fibrosis. Therefore, we studied WNT-5A expressions in mouse and human fibrotic livers and examined the relation between WNT-5A and various fibrosis-associated growth factors, cytokines, and extracellular matrix proteins. WNT-5A gene and protein expressions were significantly increased in fibrotic mouse and human livers compared with healthy livers. Regression or therapeutic intervention in mice resulted in decreased hepatic WNT-5A levels paralleled by lower collagen levels. Immunohistochemical analysis showed WNT-5A staining in fibrotic septa colocalizing with desmin staining indicating WNT-5A expression in myofibroblasts. In vitro studies confirmed WNT-5A expression in this cell type and showed that TGF-β significantly enhanced WNT-5A expression in contrast to PDGF-BB and proinflammatory cytokines IL-1β and TNF-α. Additionally, TGF-β induces the expression of the WNT receptors FZD2 and FZD8. After silencing of WNT-5A, reduced levels of collagen type I, vimentin, and fibronectin in TGF-β-stimulated myofibroblasts were measured compared with nonsilencing siRNA-treated controls. Interestingly, the antifibrotic cytokine IFNγ suppressed WNT-5A in vitro and in vivo. IFNγ-treated fibrotic mice showed significantly less WNT-5A expression compared with untreated fibrotic mice. In conclusion, WNT-5A paralleled collagen I levels in fibrotic mouse and human livers. WNT-5A expression in myofibroblasts is induced by the profibrotic factor TGF-β and plays an important role in TGF-β-induced regulation of fibrotic matrix proteins, whereas its expression can be reversed upon treatment, both in vitro and in vivo. NEW & NOTEWORTHY This study describes the localization and functional role of WNT-5A in human and mouse fibrotic livers. Hepatic WNT-5A expression parallels collagen type I expression. In vivo and in vitro, the myofibroblasts were identified as the key hepatic cells producing WNT-5A. WNT-5A is under control of TGF-β and its activities are primarily profibrotic.

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Immunity to pathogenic free-living amoebae: role of cell-mediated immunity

Infection and Immunity ◽

10.1128/iai.29.2.408-410.1980 ◽

1980 ◽

Vol 29 (2) ◽

pp. 408-410

Author(s):

R T Cursons ◽

T J Brown ◽

E A Keys ◽

K M Moriarty ◽

D Till

Keyword(s):

Immune System ◽

Inhibition Test ◽

Delayed Hypersensitivity ◽

Cell Mediated Immunity ◽

Pathogenic Species ◽

Free Living

The role of cell-mediated immunity in defense against pathogenic free-living amoebae was examined. Both the in vitro macrophage inhibition test and the in vivo delayed hypersensitivity test showed responses to both heterologous and homologous antigens, although homologous systems were the most efficient. It is suggested that exposure to nonpathogenic species of free-living amoebae can stimulate the immune system to be effective against pathogenic species. The significance of cell-mediated immunity as a defense against invasion by pathogenic free-living amoebae is discussed.

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Functional genetic encoding of sulfotyrosine in mammalian cells

Nature Communications ◽

10.1038/s41467-020-18629-9 ◽

2020 ◽

Vol 11 (1) ◽

Author(s):

Xinyuan He ◽

Yan Chen ◽

Daisy Guiza Beltran ◽

Maia Kelly ◽

Bin Ma ◽

...

Keyword(s):

Mammalian Cells ◽

Biochemical Characterization ◽

Trna Synthetase ◽

Functional Verification ◽

Cellular Processes ◽

Genetic Encoding ◽

Efficient Expression

Abstract Protein tyrosine O-sulfation (PTS) plays a crucial role in extracellular biomolecular interactions that dictate various cellular processes. It also involves in the development of many human diseases. Regardless of recent progress, our current understanding of PTS is still in its infancy. To promote and facilitate relevant studies, a generally applicable method is needed to enable efficient expression of sulfoproteins with defined sulfation sites in live mammalian cells. Here we report the engineering, in vitro biochemical characterization, structural study, and in vivo functional verification of a tyrosyl-tRNA synthetase mutant for the genetic encoding of sulfotyrosine in mammalian cells. We further apply this chemical biology tool to cell-based studies on the role of a sulfation site in the activation of chemokine receptor CXCR4 by its ligand. Our work will not only facilitate cellular studies of PTS, but also paves the way for economical production of sulfated proteins as therapeutic agents in mammalian systems.

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Integrin α10, a Novel Therapeutic Target in Glioblastoma, Regulates Cell Migration, Proliferation, and Survival

Cancers ◽

10.3390/cancers11040587 ◽

2019 ◽

Vol 11 (4) ◽

pp. 587 ◽

Cited By ~ 8

Author(s):

Matilda Munksgaard Thorén ◽

Katarzyna Chmielarska Masoumi ◽

Cecilia Krona ◽

Xiaoli Huang ◽

Soumi Kundu ◽

...

Keyword(s):

Cell Death ◽

Therapeutic Target ◽

Functional Role ◽

Treatment Strategies ◽

Antibody Drug Conjugate ◽

Potential Therapeutic Target ◽

Sphere Formation

New, effective treatment strategies for glioblastomas (GBMs), the most malignant and invasive brain tumors in adults, are highly needed. In this study, we investigated the potential of integrin α10β1 as a therapeutic target in GBMs. Expression levels and the role of integrin α10β1 were studied in patient-derived GBM tissues and cell lines. The effect of an antibody–drug conjugate (ADC), an integrin α10 antibody conjugated to saporin, on GBM cells and in a xenograft mouse model was studied. We found that integrin α10β1 was strongly expressed in both GBM tissues and cells, whereas morphologically unaffected brain tissues showed only minor expression. Partial or no overlap was seen with integrins α3, α6, and α7, known to be expressed in GBM. Further analysis of a subpopulation of GBM cells selected for high integrin α10 expression demonstrated increased proliferation and sphere formation. Additionally, siRNA-mediated knockdown of integrin α10 in GBM cells led to decreased migration and increased cell death. Furthermore, the ADC reduced viability and sphere formation of GBM cells and induced cell death both in vitro and in vivo. Our results demonstrate that integrin α10β1 has a functional role in GBM cells and is a novel, potential therapeutic target for the treatment of GBM.

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Role of macrophage CD44 in the disposal of inflammatory cell corpses*

Clinical Science ◽

10.1042/cs1030441 ◽

2002 ◽

Vol 103 (5) ◽

pp. 441-449 ◽

Cited By ~ 1

Author(s):

Sharon VIVERS ◽

Ian DRANSFIELD ◽

Simon P. HART

Keyword(s):

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Surrounding Tissue ◽

Human Macrophage ◽

Neutrophil Granulocytes ◽

Apoptotic Cells ◽

Tissue Destruction

Understanding the cellular and molecular mechanisms that determine whether inflammation resolves or progresses to scarring and tissue destruction should lead to the development of effective therapeutic strategies for inflammatory diseases. Apoptosis of neutrophil granulocytes is an important determinant of the resolution of inflammation, providing a mechanism for down-regulation of function and triggering clearance by macrophages without inducing a pro-inflammatory response. However, if the rate of cell death by apoptosis is such that the macrophage clearance capacity is exceeded, apoptotic cells may progress to secondary necrosis, resulting in the release of harmful cellular contents and in damage to the surrounding tissue. There are many possible ways in which the rate and capacity of the macrophage-mediated clearance of apoptotic cells may be enhanced or suppressed. Ligation of human macrophage surface CD44 by bivalent monoclonal antibodies rapidly and profoundly augments the capacity of macrophages to phagocytose apoptotic neutrophils in vitro. The molecular mechanism behind this effect and its potential significance in vivo is a current focus of research.

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Biologic consequences of androgen receptor (AR) activity in MDV3100-resistant LNCaP cells and dependence on AR full length.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.74 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 74-74

Author(s):

Yoshiaki Yamamoto ◽

Yohann Loriot ◽

Eliana Beraldi ◽

Tianyuan Zhou ◽

Youngsoo Kim ◽

...

Keyword(s):

Gene Expression ◽

Androgen Receptor ◽

Cell Growth ◽

Functional Role ◽

Full Length ◽

Lncap Cells ◽

Exon 1

74 Background: While recent reports link androgen receptor (AR) variants (AR-Vs) to castration resistant prostate cancer (CRPC), the biological significance of AR-Vs in AR-regulated cell survival and proliferation, independent of AR full length (AR-FL), remains controversial. To define the functional role of AR-FL and AR-Vs in MDV3100-resistant (MDV-R), we designed antisense oligonucleotide (ASO) targeting exon 1 and exon 8 in AR to knockdown AR-FL alone or in combination with AR-Vs and examined these effects in MDV-R LNCaP-derived cells in vitro and in vivo. Methods: We generated by selection MDV-R LNCaP-derived sub-lines that uniformly expressed high levels of both AR-FL and AR-V7 compared to CRPC LNCaP xenografts. Cell growth rates, protein and gene expression were analyzed using crystal violet assay, western blotting and real-time PCR, respectively. Exon 1 and 8 AR-ASO were evaluated in MDV-R49F CRPC LNCaP xenografts. Results: AR-V7 was transiently transfected in MDV-R49F cells and differential knockdown of AR-V7 and/or AR-FL by exon 1 versus exon 8 AR-ASO was used to evaluate relative biologic contributions of AR-FL versus AR-V7 in MDV-R LNCaP AR-V7 overexpressing cells. Exon 1 and 8 AR-ASO treatment in these cells similarly decreased prostate-specific antigen (PSA) expression and induced apoptosis as measured by caspase-3 and PARP cleavage and cell growth inhibition. To further define the functional role of AR-Vs in MDV-R LNCaP cells, we used a CE3 siRNA that specifically silenced AR-V7, but not AR-FL in MDV-R LNCaP cells. AR-V7 knockdown did not decrease PSA levels, did not induce apoptosis, and did not inhibit cell growth. In MDV-R LNCaP cells, exon 1 and 8 ASO similarly suppressed cell growth and AR-regulated gene expression in vitro and in vivo. Conclusions: These results indicate that the AR remains an important driver of MDV3100 resistance and, the biologic consequences mainly driven by AR-FL in MDV-R LNCaP models.

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Up-regulation of MicroRNA-21 Mediates Isoflurane-induced Protection of Cardiomyocytes

Anesthesiology ◽

10.1097/aln.0000000000000567 ◽

2015 ◽

Vol 122 (4) ◽

pp. 795-805 ◽

Cited By ~ 29

Author(s):

Jessica M. Olson ◽

Yasheng Yan ◽

Xiaowen Bai ◽

Zhi-Dong Ge ◽

Mingyu Liang ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Messenger Rna ◽

Functional Role ◽

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Cell Death Protein

Abstract Background: Anesthetic cardioprotection reduces myocardial infarct size after ischemia–reperfusion injury. Currently, the role of microRNA in this process remains unknown. MicroRNAs are short, noncoding nucleotide sequences that negatively regulate gene expression through degradation or suppression of messenger RNA. In this study, the authors uncovered the functional role of microRNA-21 (miR-21) up-regulation after anesthetic exposure. Methods: MicroRNA and messenger RNA expression changes were analyzed by quantitative real-time polymerase chain reaction in cardiomyocytes after exposure to isoflurane. Lactate dehydrogenase release assay and propidium iodide staining were conducted after inhibition of miR-21. miR-21 target expression was analyzed by Western blot. The functional role of miR-21 was confirmed in vivo in both wild-type and miR-21 knockout mice. Results: Isoflurane induces an acute up-regulation of miR-21 in both in vivo and in vitro rat models (n = 6, 247.8 ± 27.5% and 258.5 ± 9.0%), which mediates protection to cardiomyocytes through down-regulation of programmed cell death protein 4 messenger RNA (n = 3, 82.0 ± 4.9% of control group). This protective effect was confirmed by knockdown of miR-21 and programmed cell death protein 4 in vitro. In addition, the protective effect of isoflurane was abolished in miR-21 knockout mice in vivo, with no significant decrease in infarct size compared with nonexposed controls (n = 8, 62.3 ± 4.6% and 56.2 ± 3.2%). Conclusions: The authors demonstrate for the first time that isoflurane mediates protection of cardiomyocytes against oxidative stress via an miR-21/programmed cell death protein 4 pathway. These results reveal a novel mechanism by which the damage done by ischemia/reperfusion injury may be decreased.

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The Role of IL-1βin the Bone Loss during Rheumatic Diseases

Mediators of Inflammation ◽

10.1155/2015/782382 ◽

2015 ◽

Vol 2015 ◽

pp. 1-10 ◽

Cited By ~ 63

Author(s):

Piero Ruscitti ◽

Paola Cipriani ◽

Francesco Carubbi ◽

Vasiliki Liakouli ◽

Francesca Zazzeroni ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Rheumatic Diseases ◽

Nuclear Factor Kappa B ◽

Inflammatory Diseases ◽

Receptor Activator ◽

Main Factor

Several inflammatory diseases have been associated with increased bone resorption and fracture rates and different studies supported the relation between inflammatory cytokines and osteoclast activity. The main factor required for osteoclast activation is the stimulation by receptor activator of nuclear factor kappa-B ligand (RANKL) expressed on osteoblasts. In this context, interleukin- (IL-) 1β, one of the most powerful proinflammatory cytokines, is a strong stimulator of in vitro and in vivo bone resorption via upregulation of RANKL that stimulates the osteoclastogenesis. The resulting effects lead to an imbalance in bone metabolism favouring bone resorption and osteoporosis. In this paper, we review the available literature on the role of IL-1βin the pathogenesis of bone loss. Furthermore, we analysed the role of IL-1βin bone resorption during rheumatic diseases and, when available, we reported the efficacy of anti-IL-1βtherapy in this field.

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Negative Regulation of NF-κB Signaling by PIAS1

Molecular and Cellular Biology ◽

10.1128/mcb.25.3.1113-1123.2005 ◽

2005 ◽

Vol 25 (3) ◽

pp. 1113-1123 ◽

Cited By ~ 98

Author(s):

Bin Liu ◽

Randy Yang ◽

Kelly A. Wong ◽

Crescent Getman ◽

Natalie Stein ◽

...

Keyword(s):

Inflammatory Diseases ◽

Gene Activation ◽

Binding Activity ◽

Negative Regulator ◽

Necrosis Factor Alpha ◽

Dna Binding Activity ◽

Important Negative Regulator ◽

Cytokine Stimulation

ABSTRACT The NF-κB family of transcription factors is activated by a wide variety of signals to regulate a spectrum of cellular processes. The proper regulation of NF-κB activity is critical, since abnormal NF-κB signaling is associated with a number of human illnesses, such as chronic inflammatory diseases and cancer. We report here that PIAS1 (protein inhibitor of activated STAT1) is an important negative regulator of NF-κB. Upon cytokine stimulation, the p65 subunit of NF-κB translocates into the nucleus, where it interacts with PIAS1. The binding of PIAS1 to p65 inhibits cytokine-induced NF-κB-dependent gene activation. PIAS1 blocks the DNA binding activity of p65 both in vitro and in vivo. Consistently, chromatin immunoprecipitation assays indicate that the binding of p65 to the promoters of NF-κB-regulated genes is significantly enhanced in Pias1 −/− cells. Microarray analysis indicates that the removal of PIAS1 results in an increased expression of a subset of NF-κB-mediated genes in response to tumor necrosis factor alpha and lipopolysaccharide. Consistently, Pias1 null mice showed elevated proinflammatory cytokines. Our results identify PIAS1 as a novel negative regulator of NF-κB.

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