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No conflicts of Interest Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer

Nymann Dehn
· 3 min read
No conflicts of Interest Novel Genetic Loci Related to Tumor Suppression, Inflammation, and Immune BACKGROUND: Tobacco smoking is an established risk factor for colorectal cancer

However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer. METHODS: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia. RESULTS: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p1 (rs9880919, P = 58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 25; 95% confidence interval (CI), 20-30] compared with the other genotypes (OR <17 for GA and AA). Among ever smokers,  aloe emodin solubility  observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p33 (rs4151657, P = 72 × 10-8) and 8q23 (rs7005722, P = 88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 12; 95% CI, 09-16) compared with the other genotypes (OR <06 for TC and CC).

Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 17; 95% CI, 07-28) compared with the other genotypes (OR <13 for AC and CC). Functional annotation revealed that SNPs in 3p1 and 6p33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p1) and ATF6B (6p33). CONCLUSIONS: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response. IMPACT: These findings can guide the Czech Academy of Sciences, Prague, and Biomedical Center, Medical Faculty, Association for Cancer Research, cosponsored by the American Society of Extracellular signal-regulated kinase 3 (ERK3) is a poorly characterized member of the mitogen-activated protein (MAP) kinase family. Functional analysis of the ERK3 signaling pathway has been hampered by a lack of knowledge about the substrates and downstream effectors of the kinase. Here, we used large-scale quantitative phosphoproteomics and targeted gene silencing to identify direct ERK3 substrates and gain insight into its cellular functions.

Detailed validation of one candidate substrate identified the gelsolin/villin family member supervillin (SVIL) as a bona fide ERK3 substrate. We show that ERK3 phosphorylates SVIL on Ser245 to regulate myosin II activation and cytokinesis completion in dividing cells. Depletion of SVIL or ERK3 leads to increased cytokinesis failure and multinucleation, a phenotype rescued by wild type SVIL but not by the non-phosphorylatable S245A mutant. Our results unveil a new function of the atypical MAP kinase ERK3 in cell division and the regulation of early-onset autosomal dominant dementia with amyloid load and parkinsonism. INTRODUCTION: Patients with familial early-onset dementia (EOD) pose a unique opportunity for gene identification studies. METHODS: We present the phenotype and whole-exome sequencing (WES) study of an autosomal dominant EOD family. Candidate genes were examined in a set of dementia cases and controls (n = 3712).

Western blotting was conducted of the wild-type and mutant protein of the final candidate. RESULTS: Age at disease onset was 60 years (range 56 to 63). The phenotype comprised mixed amnestic and behavioral features, and parkinsonism. Cerebrospinal fluid and plasma biomarkers, and a positron emission tomography amyloid study suggested Alzheimer's disease. WES and the segregation pattern pointed to a nonsense mutation in the TRIM25 gene (p.C168*), coding for an E3 ubiquitin ligase, which was absent in the cohorts studied. Protein studies supported a loss-of-function mechanism.

DISCUSSION: This study supports a new physiopathological mechanism for brain amyloidosis. Furthermore, it extends the role of E3 ubiquitin ligases dysfunction in the development of neurodegenerative diseases. HIGHLIGHTS: A TRIM25 nonsense mutation (p.C168*) is associated with autosomal dominant early-onset dementia and parkinsonism with biomarkers suggestive of Alzheimer's disease. TRIM25 protein studies support that the mutation exerts its effect through loss of function. TRIM25, an E3 ubiquitin ligase, is known for its role in the innate immune response but this is the first report of association with neurodegeneration.  aloe emodin solubility  of TRIM25 dysfunction in development of amyloidosis and neurodegeneration merits a new line of research.

International Institute of Molecular and Cell Biology in Warsaw, Warsaw, Poland. Accurate, and Visual Naked-Eye Detection of SARS-CoV- The COVID-19 pandemic has spread to every corner of the world and seriously affected our health and daily activities in the past three years; thereby, it is still urgent to develop various simple, quick, and accurate methods for early detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission.