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Gene expression analysis of murine wt and Nbeal2 -/- bone marrow derived mast cells (BMMCs) w/o IL-33 treatment

ABSTRACT: The Neurobeachin-like 2 (Nbeal2) protein is a BEACH (beige and chediak-higashi) family member. Loss of function mutations of the human NBEAL2 gene result in development of the gray platelet syndrome (GPS) a bleeding disorder characterized by macrothrombocytopenia, splenomegaly, and paucity of Î±-granules in megakaryocytes, platelets, mast cells (MCs), neutrophils and NK cells. We found that Nbeal2 deficiency in MCs leads to an enhanced resistance to growth factor deprivation, dysregulated distribution of c-Kit and of the multidrug resistant protein-1 (ABCB1), as well as to a pro-inflammatory MC-phenotype. These characteristics are caused by a defective protein degradation machinery resulting in accumulation of RSK and ribosomal proteins (RPS). These data demonstrate that Nbeal2 prevents oncogenic transformation by controlling protein homeostasis (proteostasis) in MCs.

ORGANISM(S): Mus musculus

PROVIDER: GSE225692 | GEO | 2024/02/06

REPOSITORIES: GEO

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Project description:The p90 ribosomal S6 kinase (RSK) family, a downstream target of Ras/extracellular signal-regulated kinase (ERK) signaling, can mediate cross-talk with the mammalian target of rapamycin complex 1 (mTORC1) pathway. As RSK connects two oncogenic pathways in gliomas, we investigated the protein levels of the RSK isoforms RSK1-4 in non-tumoral brain (NB) and grade I-IV gliomas. RSK4 expression was not detected in any brain tissues, whereas RSK3 expression was very low, with GBMs demonstrating the lowest RSK3 protein levels. When compared to NB or low-grade gliomas (LGG), a group of glioblastomas (RSK1hi) that excluded long-survivor cases expressed higher levels of RSK1. No difference was observed in RSK2 median-expression levels among NB and gliomas; however, high levels of RSK2 in glioblastomas (GBM) were associated with worse survival. RSK1hi and, to a lesser extent, RSK2hi GBMs, showed higher levels of phosphorylated RSK, which indicates RSK activation. Transcriptome analysis indicated that most RSK1hi GBMs belonged to the mesenchymal subtype, and RSK1 expression strongly correlated with gene expression signature of immune infiltrates, in particular of activated-natural killer cells and M2 macrophages. In an independent cohort, we confirmed that RSK1hi GBMs exclude long-survivors, and RSK1 expression was associated with high protein levels of the mesenchymal subtype marker LAPTM5, as well as with high expression of CD68, which indicated the presence of infiltrating immune cells. An RSK1 signature was obtained based on differentially expressed mRNAs and validated in public glioma datasets. Enrichment of RSK1 signature followed glioma progression, recapitulating RSK1 protein expression, and was associated with worse survival not only in GBM but also in LGG. In conclusion, both RSK1 and RSK2 associate with glioma malignity, but displaying isoform-specific peculiarities. The progression-dependent expression and association with immune infiltration, suggests RSK1 as a potential progression marker and therapeutic target for gliomas.

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Gene expression analysis of murine wt and Nbeal2 -/- bone marrow derived mast cells (BMMCs) w/o IL-33 treatment

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