111,845 research outputs found
FOXO3 on the Road to Longevity: Lessons From SNPs and Chromatin Hubs
No full textHealth span is driven by a precise interplay between genes and the environment. Cell response to environmental cues is mediated by signaling cascades and genetic variants that affect gene expression by regulating chromatin plasticity. Indeed, they can promote the interaction of promoters with regulatory elements by forming active chromatin hubs. FOXO3 encodes a transcription factor with a strong impact on aging and age-related phenotypes, as it regulates stress response, therefore affecting lifespan. A significant association has been shown between human longevity and several FOXO3 variants located in intron 2. This haplotype block forms a putative aging chromatin hub in which FOXO3 has a central role, as it modulates the physical connection and activity of neighboring genes involved in age-related processes. Here we describe the role of FOXO3 and its single-nucleotide polymorphisms (SNPs) in healthy aging, with a focus on the enhancer region encompassing the SNP rs2802292, which upregulates FOXO3 expression and can promote the activity of the aging hub in response to different stress stimuli. FOXO3 protective effect on lifespan may be due to the accessibility of this region to transcription factors promoting its expression. This could in part explain the differences in FOXO3 association with longevity between genders, as its activity in females may be modulated by estrogens through estrogen receptor response elements located in the rs2802292-encompassing region. Altogether, the molecular mechanisms described here may help establish whether the rs2802292 SNP can be taken advantage of in predictive medicine and define the potential of targeting FOXO3 for age-related diseases
Valutazione fenologica e produttiva di camomilla (Chamomilla recutita Rauschert) sottoposta a differenti profondità di lavorazione del suolo
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Influenza delle lavorazioni del suolo su parametri qualiquantitativi del Rosmarinus Officinalis L. e sulla flora infestante
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Influenza della pacciamatura su parametri quanti-qualitativi del Rosmarinus Officinalis L.
No full textInfluenza della profondità di lavorazione su parametri biometrici di Salvia officinalis L.
No full textauthor-bios-SRD-19-0063.R1 – Supplemental material for The Network Structure of Police Misconduct
No full textSupplemental material, author-bios-SRD-19-0063.R1 for The Network Structure of Police Misconduct by George Wood, Daria Roithmayr and Andrew V. Papachristos in Socius</p
The MAPK/C-Myc Axis in CRC: new pathogenic mechanisms and therapeutic approaches
No full textIntroduction
c-Myc plays a central role in cellular proliferation, differentiation, and apoptosis. Therefore its deregulation represents a powerful trigger of tumorigenesis, particularly in colorectal cancer (CRC). It has been shown that the MEK/ERK pathway phosphorylates c-Myc on serine 62, which stabilizes c-Myc by preventing ubiquitin/proteasomal degradation. We recently reported that MEK/ERK inhibition is counteracted by over-activation of p38α MAPK. Here, we identified cellular mechanisms that lead to c-Myc deregulation, which is a crucial issue for improving CRC treatment and survival.
Materials and Methods
The cross-talk between p38α and ERK was assessed in CRC cell lines and in APCMin/+ mice, a murine model of familial adenomatous polyposis. To this aim, animals were treated with the p38α inhibitor 4-(4-Fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)-1H-imidazole (SB202190®) alone or in combination with the MEK1 inhibitor N-[(2R)-2,3-Dihydroxypropoxy]-3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]-benzamide (PD0325901®). In order to evaluate the role of p38α and ERK in c-Myc regulation, we used pharmacological inhibitors of these two kinases alone or in combination with inhibitors of the transcriptional mechanism, translational process and proteasome in CRC cell lines. Moreover, the function of p38α and ERK in Myc stabilization was assessed by genetic ablation.
Results and Discussion
Here we show that concomitant inhibition of the p38α and MEK/ERK pathways significantly increases the survival of APCMin/+ mice in which tumorigenesis is driven by c-Myc deregulation.
Genetic ablation of p38α and ERK revealed that these two MAPKs do not regulate c-Myc expression, nor do they affect c-Myc protein translational process.
We found that p38α and ERK collaborate in c-Myc stabilization by inhibiting its proteasomal degradation in CRC cell lines. These results were also confirmed by using the p38α and ERK pharmacological inhibitors LY2228820 (Ralimetinib®) and GSK1120212 (Mekinist®), respectively, which are currently in clinical trials for inflammatory diseases and cancer.
Conclusion
Since c-MYC supports the processes required for normal growth and homeostasis, its ablation is less attractive than modulation of its expression or function. Our results confirmed the essential role of the MAPK/c-Myc axis in intestinal tumorigenesis regulation, suggesting MAPK manipulation as a potential therapeutic approach to counteract c-Myc dependent carcinogenesis
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