scholarly journals Manipulation of JAK/STAT Signalling by High-Risk HPVs: Potential Therapeutic Targets for HPV-Associated Malignancies

Viruses ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 977 ◽  
Author(s):  
Ethan L. Morgan ◽  
Andrew Macdonald
Keyword(s):  
Immune Response ◽  
Cell Proliferation ◽  
Significant Proportion ◽  
Human Papillomaviruses ◽  
Janus Kinase ◽  
Signalling Pathways ◽  
Proliferative Potential ◽  
Promote Cell Proliferation ◽  
Wide Range ◽  
Stat Pathway

Human papillomaviruses (HPVs) are small, DNA viruses that cause around 5% of all cancers in humans, including almost all cervical cancer cases and a significant proportion of anogenital and oral cancers. The HPV oncoproteins E5, E6 and E7 manipulate cellular signalling pathways to evade the immune response and promote virus persistence. The Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway has emerged as a key mediator in a wide range of important biological signalling pathways, including cell proliferation, cell survival and the immune response. While STAT1 and STAT2 primarily drive immune signalling initiated by interferons, STAT3 and STAT5 have widely been linked to the survival and proliferative potential of a number of cancers. As such, the inhibition of STAT3 and STAT5 may offer a therapeutic benefit in HPV-associated cancers. In this review, we will discuss how HPV manipulates JAK/STAT signalling to evade the immune system and promote cell proliferation, enabling viral persistence and driving cancer development. We also discuss approaches to inhibit the JAK/STAT pathway and how these could potentially be used in the treatment of HPV-associated disease.

Janus Kinase Inhibitors: A Review of Their Application in the Vitiligo

2021 ◽  
Vol 21 ◽  
Author(s):  
Chao Niu ◽  
Hunjun Xie ◽  
Haji Akber Aisa
Keyword(s):  
Cell Proliferation ◽  
Atopic Dermatitis ◽  
Immune System ◽  
Immune Regulation ◽  
Kinase Inhibitors ◽  
Janus Kinase ◽  
Jak Inhibitors ◽  
Janus Kinase Inhibitors ◽  
Small Molecular Inhibitors ◽  
Stat Pathway

: The small-molecular inhibitors targeted JAks (JAK inhibitors), could modulate the cytokines-mediated signaling via JAK-STAT pathway, which plays a important role in immune regulation and cell proliferation. The JAK inhibitors are previously designed and synthesized to treat diseases involved with hematologic and immune system. Increasing evidence shows that they are quite effective in atopic dermatitis (AD), alopecia areata (AA), psoriasis, vitiligo, and other autoimmune-induced dermatologic conditions. Currently, many JAK inhibitors possessing anti-vitiligo activity are being investigated in laboratory and clinically. In this view, we would like to summarize so we review the applications of these inhibitors with emphasis on profile of vitiligo, clinical efficacy, dosages, development of new candidates and adverse events through available literatures.

scholarly journals Flavivirus Nonstructural Protein NS5 Dysregulates HSP90 to Broadly Inhibit JAK/STAT Signaling

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 899 ◽  
Author(s):  
Justin A. Roby ◽  
Katharina Esser-Nobis ◽  
Elyse C. Dewey-Verstelle ◽  
Marian R. Fairgrieve ◽  
Johannes Schwerk ◽  
...  
Keyword(s):  
Nonstructural Protein ◽  
Heat Shock Protein 90 ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Critical Determinant ◽  
Wide Range ◽  
Stat Signaling ◽  
Virus West Nile ◽  
Flavivirus Infection ◽  
Stat Pathway

Pathogenic flaviviruses antagonize host cell Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling downstream of interferons α/β. Here, we show that flaviviruses inhibit JAK/STAT signaling induced by a wide range of cytokines beyond interferon, including interleukins. This broad inhibition was mapped to viral nonstructural protein 5 (NS5) binding to cellular heat shock protein 90 (HSP90), resulting in reduced Janus kinase–HSP90 interaction and thus destabilization of unchaperoned JAKs (and other kinase clients) of HSP90 during infection by Zika virus, West Nile virus, and Japanese encephalitis virus. Our studies implicate viral dysregulation of HSP90 and the JAK/STAT pathway as a critical determinant of cytokine signaling control during flavivirus infection.

A Sensitized Genetic Screen to Identify Novel Regulators and Components of the Drosophila Janus Kinase/Signal Transducer and Activator of Transcription Pathway

Genetics ◽  
2003 ◽  
Vol 165 (3) ◽  
pp. 1149-1166
Author(s):  
Erika A Bach ◽  
Stephane Vincent ◽  
Martin P Zeidler ◽  
Norbert Perrimon
Keyword(s):  
Transgenic Line ◽  
Transgenic Animals ◽  
Cell Number ◽  
Janus Kinase ◽  
Compound Eyes ◽  
Signal Transducer ◽  
Wide Range ◽  
Proliferation And Differentiation ◽  
Stat Transcription Factor ◽  
Stat Pathway

Abstract The JAK/STAT pathway exerts pleiotropic effects on a wide range of developmental processes in Drosophila. Four key components have been identified: Unpaired, a secreted ligand; Domeless, a cytokine-like receptor; Hopscotch, a JAK kinase; and Stat92E, a STAT transcription factor. The identification of additional components and regulators of this pathway remains an important issue. To this end, we have generated a transgenic line where we misexpress the upd ligand in the developing Drosophila eye. GMR-upd transgenic animals have dramatically enlarged eye-imaginal discs and compound eyes that are normally patterned. We demonstrate that the enlarged-eye phenotype is a result of an increase in cell number, and not cell volume, and arises from additional mitoses in larval eye discs. Thus, the GMR-upd line represents a system in which the proliferation and differentiation of eye precursor cells are separable. Removal of one copy of stat92E substantially reduces the enlarged-eye phenotype. We performed an F1 deficiency screen to identify dominant modifiers of the GMR-upd phenotype. We have identified 9 regions that enhance this eye phenotype and two specific enhancers: C-terminal binding protein and Daughters against dpp. We also identified 20 regions that suppress GMR-upd and 13 specific suppressors: zeste-white 13, pineapple eye, Dichaete, histone 2A variant, headcase, plexus, kohtalo, crumbs, hedgehog, decapentaplegic, thickveins, saxophone, and Mothers against dpp.

scholarly journals An immunoevasive strategy through clinically-relevant pan-cancer genomic and transcriptomic alterations of JAK-STAT signaling components

2019 ◽  
Author(s):  
Wai Hoong Chang ◽  
Alvina G. Lai
Keyword(s):  
Genetic Alterations ◽  
Janus Kinase ◽  
Renal Tumors ◽  
Molecular Features ◽  
Wide Range ◽  
Stat Signaling ◽  
Cancer Types ◽  
Endometrial Cancers ◽  
Pan Cancer ◽  
Stat Pathway

Since its discovery almost three decades ago, the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway has paved the road for understanding inflammatory and immunity processes related to a wide range of human pathologies including cancer. Several studies have demonstrated the importance of JAK-STAT pathway components in regulating tumor initiation and metastatic progression, yet, the extent of how genetic alterations influence patient outcome is far from being understood. Focusing on 133 genes involved in JAK-STAT signaling, we found that copy number alterations underpin transcriptional dysregulation that differs within and between cancer types. Integrated analyses on over 18,000 tumors representing 21 cancer types revealed a core set of 28 JAK-STAT pathway genes that correlated with survival outcomes in brain, renal, lung and endometrial cancers. High JAK-STAT scores were associated with increased mortality rates in brain and renal cancers, but not in lung and endometrial cancers where hyperactive JAK-STAT signaling is a positive prognostic factor. Patients with aberrant JAK-STAT signaling demon-strated pan-cancer molecular features associated with misex-pression of genes in other oncogenic pathways (Wnt, MAPK, TGF-β, PPAR and VEGF). Brain and renal tumors with hyperactive JAK-STAT signaling had increased regulatory T cell gene (Treg) expression. A combined model uniting JAK-STAT and Tregs allowed further delineation of risk groups where patients with high JAK-STAT and Treg scores consistently performed the worst. Providing a pan-cancer perspective of clinically-relevant JAK-STAT alterations, this study could serve as a framework for future research investigating anti-tumor immunity using combination therapy involving JAK-STAT and immune checkpoint inhibitors.

Hijack and exploitation of host SOCS proteins: An immunosuppressive deception of the viruses

2014 ◽  
Vol 3 (6) ◽  
pp. 314-318
Author(s):  
Mansi Shrivastava ◽  
Sarfaraz Alam ◽  
L. K. Dwivedi
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Feedback Loop ◽  
Janus Kinase ◽  
Cytokine Signaling ◽  
Signal Transducer ◽  
Host Body ◽  
Body Tissues ◽  
Socs Proteins ◽  
Stat Pathway

The suppressors of cytokine signaling (SOCS) are a cytoplasmic protein family that completes a negative feedback loop to attenuate signal transduction from cytokines through the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. They work as a natural precaution to pre-vent excessive immune responses that could cause collateral damage to body tissues. But viruses use SOCS proteins to suppress the proportionate immune response also so that a vulnerable environment can be developed in host body to let them grow freely. In several cases, an increased expression of SOCS proteins has been reported in virus infected individuals, which is believed to be induced by the viruses to inhibit the anti-proliferative and antiviral activity of cytokines (Interferon) of host body. Viruses including HIV hijack the expression of SOCS proteins and manipulate them in a way where they support the onset of antigens in host body by suppressing the cell sig-nalling of immune response. Detailed mechanism of the same and an alter-native way to stop viral infection by restoring the normal SOCS expression is discussed in the present review.

scholarly journals Polymorphisms in the Janus kinase 2 (JAK)/signal transducer and activator of transcription (STAT) genes: putative association of the STAT gene region with familial breast cancer

2007 ◽  
Vol 14 (2) ◽  
pp. 267-277 ◽  
Author(s):  
Annika Vaclavicek ◽  
Justo Lorenzo Bermejo ◽  
Rita K Schmutzler ◽  
Christian Sutter ◽  
Barbara Wappenschmidt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Genetic Variation ◽  
Information Criterion ◽  
Janus Kinase ◽  
Gene Region ◽  
Signal Transducer ◽  
Increased Risk ◽  
Wide Range ◽  
Variant Alleles ◽  
Stat Pathway

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway mediates the signals of a wide range of cytokines, growth factors and hormones. Thus, aberrant activation of the JAK/STAT pathway may predispose to malignancy due to deregulation of proliferation, differentiation or apoptosis. In this study, we investigated whether genetic variation in the JAK2 gene and the STAT gene region (STAT3, STAT5A and STAT5B) is associated with breast cancer (BC) risk. We carried out a case-control study using a German sample set with 441 familial, unrelated BC cases and 552 controls matched by age, ethnicity and geographical region. A second similar set (381 cases, 460 controls) was applied to validate the findings. Haplotypes in the JAK2 gene were not associated with the risk of BC. In the STAT gene region, the rare haplotype CAGCC containing the variant alleles of each single nucleotide polymorphism (SNP) was associated with an increased risk odds ratio (OR = 5.83, 95% confidence interval (CI) 1.51–26.28). According to Akaike’s information criterion, the best model to describe the relationship between the haplotypes and BC was based on the SNPs rs6503691 (STAT5B) and rs7211777 (STAT3). Carriers of the AC haplotype, which represents the variant alleles of both SNPs, were at an increased risk (OR = 1.41, 95% CI 1.09–1.82). A decreased risk was observed for carriers of the AT haplotype (OR = 0.60, 95% CI 0.38–0.94). Furthermore, individuals with the AC/GC diplotype were at a significantly increased risk (OR = 1.88, 95% CI 1.13–3.14). The observed genetic variation may also influence the inter-individual variation in response to STAT-signalling targeted therapy.

scholarly journals Use of Proteins Identified through a Functional Genomic Screen To Develop a Protein Subunit Vaccine That Provides Significant Protection against Virulent Streptococcus suis in Pigs

2017 ◽  
Vol 86 (3) ◽  
Author(s):  
Susan L. Brockmeier ◽  
Crystal L. Loving ◽  
Tracy L. Nicholson ◽  
Jinhong Wang ◽  
Sarah E. Peters ◽  
...  
Keyword(s):  
Immune Response ◽  
Vaccine Trial ◽  
Streptococcus Suis ◽  
Protein Subunit ◽  
Content Type ◽  
Degree Of Protection ◽  
Wide Range ◽  
Associated Proteins ◽  
Clinical Protection ◽  
Cellular Immune

ABSTRACT Streptococcus suis is a bacterium that is commonly carried in the respiratory tract and that is also one of the most important invasive pathogens of swine, commonly causing meningitis, arthritis, and septicemia. Due to the existence of many serotypes and a wide range of immune evasion capabilities, efficacious vaccines are not readily available. The selection of S. suis protein candidates for inclusion in a vaccine was accomplished by identifying fitness genes through a functional genomics screen and selecting conserved predicted surface-associated proteins. Five candidate proteins were selected for evaluation in a vaccine trial and administered both intranasally and intramuscularly with one of two different adjuvant formulations. Clinical protection was evaluated by subsequent intranasal challenge with virulent S. suis . While subunit vaccination with the S. suis proteins induced IgG antibodies to each individual protein and a cellular immune response to the pool of proteins and provided substantial protection from challenge with virulent S. suis , the immune response elicited and the degree of protection were dependent on the parenteral adjuvant given. Subunit vaccination induced IgG reactive against different S. suis serotypes, indicating a potential for cross protection.

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