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Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance.

ABSTRACT: Activating mutations of G protein alpha subunits (Ga) occur in 4-5% of all human cancers1 but oncogenic alterations in beta subunits (Gb) have not been defined. Here we demonstrate that recurrent mutations in the Gb proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Ga subunits as well as downstream effectors, and disrupt Ga-Gbg interactions. Different mutations in Gb proteins clustered to some extent based on lineage; for example, all eleven GNB1 K57 mutations were in myeloid neoplasms while 6 of 7 GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 alleles in Cdkn2a-deficient bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K/mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, GNB1 mutations co-occurred with oncogenic kinase alterations, including BCR/ABL, JAK2 V617F and BRAF V600K. Co-expression of patient-derived GNB1 alleles with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 mutations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling.

ORGANISM(S): Homo sapiens

PROVIDER: GSE60990 | GEO | 2014/12/07

SECONDARY ACCESSION(S): PRJNA260048

REPOSITORIES: GEO

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Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance.

Project description:Activating mutations of G protein alpha subunits (Ga) occur in 4-5% of all human cancers1 but oncogenic alterations in beta subunits (Gb) have not been defined. Here we demonstrate that recurrent mutations in the Gb proteins GNB1 and GNB2 confer cytokine-independent growth and activate canonical G protein signaling. Multiple mutations in GNB1 affect the protein interface that binds Ga subunits as well as downstream effectors, and disrupt Ga-Gbg interactions. Different mutations in Gb proteins clustered to some extent based on lineage; for example, all eleven GNB1 K57 mutations were in myeloid neoplasms while 6 of 7 GNB1 I80 mutations were in B cell neoplasms. Expression of patient-derived GNB1 alleles in Cdkn2a-deficient bone marrow followed by transplantation resulted in either myeloid or B cell malignancies. In vivo treatment with the dual PI3K/mTOR inhibitor BEZ235 suppressed GNB1-induced signaling and markedly increased survival. In several human tumors, GNB1 mutations co-occurred with oncogenic kinase alterations, including BCR/ABL, JAK2 V617F and BRAF V600K. Co-expression of patient-derived GNB1 alleles with these mutant kinases resulted in inhibitor resistance in each context. Thus, GNB1 and GNB2 mutations confer transformed and resistance phenotypes across a range of human tumors and may be targetable with inhibitors of G protein signaling. The GM-CSF dependent human cell line TF-1 was transduced with a retrovirus expressing GNB1 K89E or empty vector. RNA was extracted from cells 12 hours after withdrawal of GM-CSF and from cells maintained in GM-CSF. Biological triplicates of each condition were performed. Gene expression differences were calculated between the four conditions.

2014-12-07 | E-GEOD-60990 | biostudies-arrayexpress

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MeDIP sequencing of Ovis aries

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2014-06-06 | E-GEOD-56644 | biostudies-arrayexpress

Homo sapiens

Project description:Mutations in G protein beta subunits promote transformation and kinase inhibitor resistance.

| PRJNA260048 | ENA

Expression analysis of Trichoderma reesei QM9414 and delta-phlp1, delta-gnb1 and delta-gng1 in light and darkness.

Project description:Investigation of whole genome gene expression level changes in response to different light conditions of the T. reesei QM9414 parental strain and the deletion strains delta-phlp1, delta-gnb1 and delta gng1, cultivated on 1 % microcrystalline cellulose. The mutants analyzed in this study are further described in Tisch et al. 2011: Carbohydrate degradation is significantly regulated by light and the phosducin like protein PhLP1 in Trichoderma reesei (Hypocrea jecorina). We used two biological replicates of four T. reesei strains (QM9414, delta-phlp1, delta-gnb1 and delta-gng1), cultivated in constant light (LL, 1800 lux) or constant darkness (DD) on microcrystalline cellulose.

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Gene regulation in Bacillus subtilis by the compatible solute glycine betaine

Project description:Glycine betaine (GB) is a potent osmoprotectant for salt stressed Bacillus subtilis cells, which possess three high-affinity uptake systems for GB. OpuA is the dominant transporter for this compatible solute. Northern blot analysis, primer extension experiments and opuA-treA reporter gene fusion studies demonstrated that opuA expression is strongly induced at high osmolality from a single SigA-type promoter. Promoter mutations that improve the match of the opuA promoter to the consensus sequence substantially increase basal-level expression but reduce inducibility by high salinity. Expression of opuA is sensitively controlled by GB, which causes significant repression of opuA transcription at low and high salinity. GB influences the kinetics as well as the final level of high salinity induction of opuA in a concentration-dependent fashion. The repressing effect of GB on opuA transcription requires the intracellular presence of GB, regardless whether it is taken up via OpuA or other transporters or synthesized from choline. Genome-wide transcriptional profiling of salt-stressed B. subtilis cells demonstrated that the repressive effect of GB targets only a subset of high-salinity induced genes. This group of GB-responsive genes comprises in essence the full set of genes with demonstrated functions in either the uptake or synthesis of compatible solutes. Four different samples (untreated, GB, NaCl, and GB + NaCl treated) were analyzed and each sample was hybridized in triplicate.

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Homo sapiens

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