Circadian rhythms are maintained by series of circadian clock proteins, and post‐translation modifications of clock proteins significantly contribute to regulating circadian clock. However, the underlying upstream mechanism of circadian genes that are responsible for circadian rhythms in cancer cells remains unknown. PIWIL1 participates in many physiological processes and current discoveries have shown that PIWIL1 is involved in tumorigenesis in various cancers. Here we report that PIWIL1 can suppress circadian rhythms in cancer cells. Mechanistically, by promoting SRC interacting with PI3K, PIWIL1 can activate PI3K‐AKT signalling pathway to phosphorylate and inactivate GSK3β, repressing GSK3β‐induced phosphorylation and ubiquitination of CLOCK and BMAL1. Simultaneously, together with CLOCK/BMAL1 complex, PIWIL1 can bind with E‐BOX region to suppress transcriptional activities of clock‐controlled genes promoters. Collectively, our findings first demonstrate that PIWIL1 negatively regulates circadian rhythms via two pathways, providing molecular connection between dysfunction of circadian rhythms and tumorigenesis.
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BackgroundThe protein encoded by the cartilage oligomeric matrix protein (COMP) gene is a noncollagenous extracellular matrix (ECM) protein that is important for chondrocyte formation and growth. Variations in the COMP gene cause pseudoachondroplasia (PSACH), which is mainly characterized by short‐limbed dwarfing in the clinic.AimsTo characterize the function of a rare pathogenic variant in the COMP gene (c.875G > A, p.Cys292Tyr).Materials & MethodsWe performed 3D structural analysis, in vitro expression analysis, and immunofluorescence to characterize the effects of the variant on protein structure, expression, and cellular localization respectively.ResultsVariation modeling showed that the interactions between amino acids were changed after the variation, and there were 31 changes in the secondary structure of mutant COMP (MT‐COMP). Western blot showed that the intracellular quantity of MT‐COMP was higher than the wild‐type COMP (WT‐COMP). Cellular immunofluorescence results showed that WT‐COMP was less abundant and homogenously distributed in cells, while the MT‐COMP accumulated in the cytoplasm.DiscussionHerein, we report a variant of COMP in a Chinese family with PSACH. We have shown that the rare missense variant, COMP c.875G > A, previously reported in ClinVar and identified in our patient, results in excessive accumulation of mutant protein in the cytoplasm, and is therefore pathogenic.ConclusionThrough in silico and experimental analyses, we provide evidence that COMP c.875G > A is the likely cause of PSACH in a Chinese family.
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