Autophagy is a starvation response that facilitates cell survival under metabolic stress and yet defects in autophagy promote tumorigenesis. While the role of understarvation is relatively clearer, its mechanistic role in tumorigenesis is poorly understood. We show that defective autophagy promotes protein damage and accumulation of p62, a marker for protein damage accumulation that is cleared through autophagy pathway. The failure to eliminate p62 in autophagy-defective cells, leads to deregulation of cell signalling and gene expression and ultimately promotes tumorigenesis. Thus defective-autophagy is a mechanism for p62 accumulation commonly observed in human tumors.
Autophagy suppresses tumorigenesis through elimination of p62.
Cell line
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ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup.
Specimen part
View SamplesGene expression profiling of PanNETs patients samples were performed to understand genotype to phenotype correlations, novel molecular subtypes and cell of origin
ATRX, DAXX or MEN1 mutant pancreatic neuroendocrine tumors are a distinct alpha-cell signature subgroup.
Specimen part
View SamplesRescuing the function of mutant p53 protein is an attractive cancer therapeutic strategy. Using the NCI anticancer drug screen data, we identified two compounds from the thiosemicarbazone family that manifest increased growth inhibitory activity in mutant p53 cells, particularly for the p53R175 mutant. Mechanistic studies reveal that NSC319726 restores WT structure and function to the p53R175 mutant. This compound kills p53R172H knock-in mice with extensive apoptosis and inhibits xenograft tumor growth in a 175-allele specific mutant p53 dependent manner. This activity depends upon the zinc ion chelating properties of the compound as well as redox changes. These data identify NSC319726 as a p53R175 mutant reactivator and as a lead compound for p53 targeted drug development.
Allele-specific p53 mutant reactivation.
Specimen part, Cell line, Treatment
View SamplesAn important cellular defense mechanism against oxidative stress is the induction of genes involved in ROS resistance and DNA damage repair. Under normal conditions, Sod1 is localized mainly in the cytosol. However, we found that Sod1 translocates into the nucleus after oxidative stress.
Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance.
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View SamplesExpression data from human induced pluripotent stem cells(iPSCs) and Human foreskin fibroblasts (HFFs) with treatment actinomycin D
Global analysis reveals multiple pathways for unique regulation of mRNA decay in induced pluripotent stem cells.
Specimen part, Treatment, Time
View SamplesAlmost all cellular mRNAs terminate in a 3 poly(A) tail, the removal of which can induce both translational silencing and mRNA decay. Mammalian cells encode many poly(A)-specific exoribonucleases but their individual roles are poorly understood. Here, we undertook an analysis of the role of PARN deadenylase in mouse myoblasts using global measurements of mRNA decay rates. Our results reveal that a discrete set of mRNAs exhibit altered mRNA decay as a result of PARN depletion and that stabilization is associated with increased poly(A) tail length and translation. We determined that stabilization of mRNAs does not generally result in their increased abundance supporting the idea that mRNA decay is coupled to transcription. Importantly, PARN knockdown has wide ranging effects on gene expression that specifically impact the extracellular matrix and cell migration. Finally, although PARN has its own unique target transcripts it also influences some genes whose expression is modulated by other deadenylases.
The PARN deadenylase targets a discrete set of mRNAs for decay and regulates cell motility in mouse myoblasts.
Specimen part, Cell line
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Systematic analysis of cis-elements in unstable mRNAs demonstrates that CUGBP1 is a key regulator of mRNA decay in muscle cells.
Specimen part, Cell line
View SamplesDramatic changes in gene expression occur in response to extracellular stimuli and during differentiation. Although transcriptional effects are important, alterations in mRNA decay also play a major role in achieving rapid and massive changes in mRNA abundance. Moreover, just as transcription factor activity varies between different cell types, the factors influencing mRNA decay are also cell-type specific. We have established the rates of decay for over 7000 transcripts expressed in mouse C2C12 myoblasts.
Systematic analysis of cis-elements in unstable mRNAs demonstrates that CUGBP1 is a key regulator of mRNA decay in muscle cells.
Specimen part, Cell line
View SamplesThe present study was to investigate the differentially expressed genes in 24-hour-old (containing proliferative cardiomyocytes), 7-day-old (containing the burst of proliferative cardiomyocytes), and 10-week-old (containing growth-arrested cardiomyocytes) C57BL/6 mouse hearts using global gene expression profiles.
Global gene expression analysis combined with a genomics approach for the identification of signal transduction networks involved in postnatal mouse myocardial proliferation and development.
Specimen part
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