SIRT2-mediated inactivation of p73 is required for glioblastoma tumorigenicity
Ontology highlight
ABSTRACT:
SUBMITTER: Dr. Kosuke Funato
PROVIDER: S-SCDT-EMBOR-2017-45587V1 | biostudies-other |
REPOSITORIES: biostudies-other
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Project description:One aspect of intra-tumoral heterogeneity in glioblastoma involves subpopulations of cells capable of self-renewal and indefinite propagation. Conceptually, this capacity is frequently treated as a static property. Here we provide data suggesting that tumorigenicity in glioblastomais a dynamic property that can be acquired or lost. Integrated expression analyses suggest that tumorigenicity is determined by the level of MYC expression relative to a threshold. Transitions between tumorigenic and non-tumorigenic cell states are associated with changes in histone modifications at the MYC locus, suggesting tumorigenicity is epigenetically regulated. To verify genomic stability at the nucleotide level, we tested whether subclones derived from single cells shared common Single-Nucleotide Polymorphisms (SNPs). Ten single cell-derived subclones of U87MG underwent SNP profiling by Affymetrix Human Mapping 250K Nsp arrays.
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Project description:Sirtuin 2 (SIRT2) is thought to be important in the pathogenesis of Parkinson's disease (PD), and the inhibition of SIRT2 rescues α-synuclein toxicity in a cellular model of PD. Recent studies have focused on identifying inhibitors of SIRT2, but little is known about the processes that directly regulate its function. GSK3β is a serine/threonine protein kinase that affects a wide range of biological functions, and it is localized in Lewy bodies (LBs). Therefore, we investigated whether SIRT2 is regulated by GSK3β and enhances cell death in PD. In the present study, Western blot showed that total SIRT2 levels did not change noticeably in a cellular model of PD but that SIRT2 phosphorylation was increased, and GSK3β activity was elevated. In addition, mass spectrometry (MS) studies indicated that SIRT2 was phosphorylated by GSK3β at three specific sites. Phospho- or dephospho-mimicking studies demonstrated that this postmodification (phosphorylation) increased SIRT2 toxicity in SH-SY5Y cells. Collectively, our findings identify a posttranslational mechanism that controls SIRT2 function in PD and provide evidence for a novel regulatory pathway involving GSK3β, SIRT2, and α-synuclein.
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