scholarly journals Genetic Variability ofCandida albicansSap8 Propeptide in Isolates from Different Types of Infection

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Joana Carvalho-Pereira ◽  
Catarina Vaz ◽  
Catarina Carneiro ◽  
Célia Pais ◽  
Paula Sampaio
Keyword(s):  
Genetic Variability ◽  
Dna Sequences ◽  
Mapk Pathway ◽  
Gene Diversity ◽  
Signal Sequence ◽  
Bloodstream Infections ◽  
Virulence Determinants ◽  
Pathway Activation ◽  
Different Types ◽  
Mature Enzyme

The secreted aspartic proteases (Saps) are among the most studied virulence determinants inCandida albicans. These proteins are translated as pre-pro-enzymes consisting of a signal sequence followed by a propeptide and the mature enzyme. The propeptides of secreted proteinases are important for the correct processing, folding/secretion of the mature enzyme. In this study, the DNA sequences ofC. albicansSaps were screened and a microsatellite was identified inSAP8propeptide region. The genetic variability of the repetitive region of Sap8 propeptide was determined in 108C. albicansindependent strains isolated from different types of infection: oral infection (OI), oral commensal (OC), vulvovaginal candidiasis (VVC), and bloodstream infections (BSI). Nine different propeptides for Sap8 processing were identified whose frequencies varied with the type of infection. OC strains presented the highest gene diversity while OI isolated the lowest. The contribution of the Saps to mucosal and systemic infections has been demonstrated and recently Sap8 has been implicated in the cleavage of a signalling glycoprotein that leads to Cek1-MAPK pathway activation. This work is the first to identify a variable microsatellite in the propeptide of a secreted aspartic protease and brings new insights into the variability of Sap8.

scholarly journals Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Sarah A. Carratt ◽  
Theodore P. Braun ◽  
Cody Coblentz ◽  
Zachary Schonrock ◽  
Rowan Callahan ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Pathway Activation

scholarly journals Cerebrospinal fluid (CSF) augments metabolism and virulence expression factors in Acinetobacter baumannii

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jasmine Martinez ◽  
Chelsea Razo-Gutierrez ◽  
Casin Le ◽  
Robert Courville ◽  
Camila Pimentel ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Acinetobacter Baumannii ◽  
Virulence Factors ◽  
Atp Synthesis ◽  
Bloodstream Infections ◽  
Model Systems ◽  
Phenotypic Traits ◽  
Virulence Determinants ◽  
Expression Of Genes

AbstractIn a recent report by the Centers for Disease Control and Prevention (CDC), multidrug resistant (MDR) Acinetobacter baumannii is a pathogen described as an “urgent threat.” Infection with this bacterium manifests as different diseases such as community and nosocomial pneumonia, bloodstream infections, endocarditis, infections of the urinary tract, wound infections, burn infections, skin and soft tissue infections, and meningitis. In particular, nosocomial meningitis, an unwelcome complication of neurosurgery caused by extensively-drug resistant (XDR) A. baumannii, is extremely challenging to manage. Therefore, understanding how A. baumannii adapts to different host environments, such as cerebrospinal fluid (CSF) that may trigger changes in expression of virulence factors that are associated with the successful establishment and progress of this infection is necessary. The present in-vitro work describes, the genetic changes that occur during A. baumannii infiltration into CSF and displays A. baumannii’s expansive versatility to persist in a nutrient limited environment while enhancing several virulence factors to survive and persist. While a hypervirulent A. baumannii strain did not show changes in its transcriptome when incubated in the presence of CSF, a low-virulence isolate showed significant differences in gene expression and phenotypic traits. Exposure to 4% CSF caused increased expression of virulence factors such as fimbriae, pilins, and iron chelators, and other virulence determinants that was confirmed in various model systems. Furthermore, although CSF's presence did not enhance bacterial growth, an increase of expression of genes encoding transcription, translation, and the ATP synthesis machinery was observed. This work also explores A. baumannii’s response to an essential component, human serum albumin (HSA), within CSF to trigger the differential expression of genes associated with its pathoadaptibility in this environment.

scholarly journals trans-Fatty acids promote p53-dependent apoptosis triggered by cisplatin-induced DNA interstrand crosslinks via the Nox-RIP1-ASK1-MAPK pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yusuke Hirata ◽  
Miki Takahashi ◽  
Yuto Yamada ◽  
Ryosuke Matsui ◽  
Aya Inoue ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mapk Pathway ◽  
Regulatory Protein ◽  
Strand Break ◽  
Mitogen Activated Protein Kinase ◽  
Ros Generation ◽  
Apoptotic Pathway ◽  
Interstrand Crosslinks ◽  
Pathway Activation ◽  
Dna Interstrand Crosslinks

Abstracttrans-Fatty acids (TFAs) are food-derived fatty acids associated with various diseases including cardiovascular diseases. However, the underlying etiology is poorly understood. Here, we show a pro-apoptotic mechanism of TFAs such as elaidic acid (EA), in response to DNA interstrand crosslinks (ICLs) induced by cisplatin (CDDP). We previously reported that TFAs promote apoptosis induced by doxorubicin (Dox), a double strand break (DSB)-inducing agent, via a non-canonical apoptotic pathway independent of tumor suppressor p53 and apoptosis signal-regulating kinase (ASK1), a reactive oxygen species (ROS)-responsive kinase. However, here we found that in the case of CDDP-induced apoptosis, EA-mediated pro-apoptotic action was reversed by knockout of either p53 or ASK1, despite no increase in p53 apoptotic activity. Upon CDDP treatment, EA predominantly enhanced ROS generation, ASK1-p38/c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase (MAPK) pathway activation, and ultimately cell death, all of which were suppressed either by co-treatment of the NADPH oxidase (Nox) inhibitor Apocynin, or by knocking out its regulatory protein, receptor-interacting protein 1 (RIP1). These results demonstrate that in response to CDDP ICLs, TFAs promote p53-dependent apoptosis through the enhancement of the Nox-RIP1-ASK1-MAPK pathway activation, providing insight into the diverse pathogenetic mechanisms of TFAs according to the types of DNA damage.

scholarly journals BRAFDuplications and MAPK Pathway Activation Are Frequent in Gliomas of the Optic Nerve Proper

2012 ◽  
Vol 71 (9) ◽  
pp. 789-795 ◽  
Author(s):  
Fausto J. Rodriguez ◽  
Azra H. Ligon ◽  
Iren Horkayne-Szakaly ◽  
Elisabeth J. Rushing ◽  
Keith L. Ligon ◽  
...  
Keyword(s):  
Optic Nerve ◽  
Mapk Pathway ◽  
Pathway Activation

scholarly journals Activating mutations in BRAF disrupt the hypothalamo-pituitary axis leading to hypopituitarism in mice and humans

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Angelica Gualtieri ◽  
Nikolina Kyprianou ◽  
Louise C. Gregory ◽  
Maria Lillina Vignola ◽  
James G. Nicholson ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Critical Role ◽  
Cell Lineage ◽  
Activating Mutations ◽  
Pathway Activation ◽  
Tumour Formation ◽  
Conditional Expression ◽  
Cell Cycle Inhibitors ◽  
Mutation Braf

AbstractGermline mutations in BRAF and other components of the MAPK pathway are associated with the congenital syndromes collectively known as RASopathies. Here, we report the association of Septo-Optic Dysplasia (SOD) including hypopituitarism and Cardio-Facio-Cutaneous (CFC) syndrome in patients harbouring mutations in BRAF. Phosphoproteomic analyses demonstrate that these genetic variants are gain-of-function mutations leading to activation of the MAPK pathway. Activation of the MAPK pathway by conditional expression of the BrafV600E/+ allele, or the knock-in BrafQ241R/+ allele (corresponding to the most frequent human CFC-causing mutation, BRAF p.Q257R), leads to abnormal cell lineage determination and terminal differentiation of hormone-producing cells, causing hypopituitarism. Expression of the BrafV600E/+ allele in embryonic pituitary progenitors leads to an increased expression of cell cycle inhibitors, cell growth arrest and apoptosis, but not tumour formation. Our findings show a critical role of BRAF in hypothalamo-pituitary-axis development both in mouse and human and implicate mutations found in RASopathies as a cause of endocrine deficiencies in humans.

Oncogenic FAM131B–BRAF fusion resulting from 7q34 deletion comprises an alternative mechanism of MAPK pathway activation in pilocytic astrocytoma

2011 ◽  
Vol 121 (6) ◽  
pp. 763-774 ◽  
Author(s):  
Huriye Cin ◽  
Claus Meyer ◽  
Ricarda Herr ◽  
Wibke G. Janzarik ◽  
Sally Lambert ◽  
...  
Keyword(s):  
Pilocytic Astrocytoma ◽  
Mapk Pathway ◽  
Alternative Mechanism ◽  
Pathway Activation ◽  
Braf Fusion

Molecular characterization of the Ras-MAPK pathway in metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1034-1034
Author(s):  
Justin Wayne Wong Tiu-lim ◽  
Jun Yin ◽  
Joanne Xiu ◽  
Wolfgang Michael Korn ◽  
Heinz-Josef Lenz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Mapk Pathway ◽  
Metastatic Breast ◽  
Molecular Alterations ◽  
Ras Genes ◽  
Mutational Status ◽  
Pathway Activation ◽  
Class 1

1034 Background: The Ras-MAPK pathway is a known driver of tumorigenesis and therapeutic target in a variety of cancers. Alterations in this pathway have been linked to decreased tumor immunogenicity. However, molecular alterations in the Ras-MAPK are rare in breast cancer (BC) and their clinical implications remain unclear. As mutational status does not accurately correlate with transcriptional activity, a MAPK pathway activity score (MPAS, Wagle et al., 2018, npj Precision Medicine) is indicative of MAPK activation and correlates with response to MEK (MEKi) or BRAF inhibition (BRAFi). Our goal was to determine the frequency of molecular alterations in the Ras-MAPK and correlate to MAPK pathway activation in MBC. Methods: A total of 6464 BC samples underwent comprehensive molecular profiling at Caris Life Sciences. Analyses included next generation sequencing of DNA (592 Gene Panel, NextSeq; whole exome sequencing, NovaSEQ), RNA (NovaSeq, whole transcriptome sequencing, WTS) and IHC. MPAS and immune cell fraction (ICF, Quantiseq) were assessed by mRNA analysis. Wilcoxon, Fisher’s exact, or Dunnett’s test was used. All results shown were statistically significant (p < 0.05). Results: The predominant alteration of RAS genes was mutation followed by amplification, no fusions were detected (Table). Only 0.17% of all tumors harbor KRAS G12c mutations. The highest MPAS scores were found in KRAS mutants (mut), HRAS mut (Q61, G1213), BRAF V600 (class 1) mut and NRAS Q61 mut (Table) and therefore used to define Genomic MAPK Activated Tumors (GMAT). GMAT compared to wild type (WT) had significantly higher PD-L1 expression, TMB and MSI/dMMR. GMAT had less B cells (3.4% vs 4.4%), more M1 Macrophages (4.4% vs 3.4%) and neutrophils (5.5% vs 2.7%) regardless of HR status but less NK cells (2.3% s 3.0%), MSDCs (0.9% vs 3.0%) only in HR- tumors with respect to WT. GMAT tumors showed more frequent mutation rate (mr) of PIK3CA (HR+: 57.3% vs 40%; HR-: 41.9% vs 17.9%). HR+ tumors had a higher mr of MSH3 (11.8% vs 0.6%) while HR- tumors had higher mr of PIK3R1 (9.6% vs 3.8%), RhoA (5.3% vs 0.5%), DNA repair genes (TERT, 18.2% vs 1.0%; ARID1A, 18.2% vs 5.9%; PRKDC, 3.9% vs 0) and lower TP53 mr (54.5% vs 85.8%) compared to WT. Conclusions: Our study demonstrates that RAS, BRAF and MEK1 mutations are associated with MAPK pathway activation indicative of benefit from MEKi or BRAFi. GMAT warrant further investigation for combinations targeting the RAS-MAPK pathway and immune checkpoint inhibitors.[Table: see text]

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