Dataset Information

Requirement for interaction of PI3-kinase p110? with RAS in lung tumor maintenance.

ABSTRACT: RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110? subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110? in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model. In established tumors, removal of the ability of p110? to interact with RAS causes long-term tumor stasis and partial regression. This is a tumor cell-autonomous effect, which is improved significantly by combination with MEK inhibition. Total removal of p110? expression or activity has comparable effects, albeit with greater toxicities.

SUBMITTER: Castellano E

PROVIDER: S-EPMC3826036 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance.

Castellano Esther E Sheridan Clare C Thin May Zaw MZ Nye Emma E Spencer-Dene Bradley B Diefenbacher Markus E ME Moore Christopher C Kumar Madhu S MS Murillo Miguel M MM Grönroos Eva E Lassailly Francois F Stamp Gordon G Downward Julian J

Cancer cell 20131101 5

RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model. In established tumors, removal of the ability of p110α to interact wi ...[more]

PMID: 24229709

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Project description:BackgroundPhosphoinositide 3-kinase ? (PI3K?) and PI3K? are second messenger-generating enzymes with key roles in proliferation, differentiation, survival, and function of leukocytes. Deficiency of the catalytic subunits p110? and p110? of PI3K? and PI3K? in p110?/?-/- mice leads to defective B- and T-cell homeostasis. Here we examined the role of p110? and p110? in the homeostasis of neutrophils by analyzing p110?-/-, p110?-/- and p110?/?-/- mice.MethodsNeutrophils and T cells in leukocyte suspensions from the bone marrow (BM), blood, spleen and lung were analyzed by flow cytometry. Serum concentrations of IL-17, of the neutrophilic growth factor G-CSF, and of the neutrophil mobilizing CXC chemokines CXCL1/KC and CXCL2/MIP-2 were measured by Bio-Plex assay. Production of G-CSF and CXCL1/KC by IL-17-stimulated primary lung tissue cells were determined by ELISA, whereas IL-17-dependent signaling in lung tissue cells was analyzed by measuring Akt phosphorylation using immunoblot.ResultsWe found that in contrast to single knock-out mice, p110?/?-/- mice exhibited significantly elevated neutrophil counts in blood, spleen, and lung. Increased granulocytic differentiation stages in the bone marrow of p110?/?-/- mice were paralleled by increased serum concentrations of G-CSF, CXCL1/KC, and CXCL2/MIP-2. As IL-17 induces neutrophilia via the induction of G-CSF and CXC chemokines, we measured IL-17 and IL-17-producing T cells. IL-17 serum concentrations and frequencies of IL-17+ splenic T cells were significantly increased in p110?/?-/- mice. Moreover, IFN-?+, IL-4+, and IL-5+ T cell subsets were drastically increased in p110?/?-/- mice, suggesting that IL-17+ T cells were up-regulated in the context of a general percentage increase of other cytokine producing T cell subsets.ConclusionsWe found that p110?/? deficiency in mice induces complex immunological changes, which might in concert contribute to neutrophilia. These findings emphasize a crucial but indirect role of both p110? and p110? in the regulation of neutrophil homeostasis.

Dataset Information

Requirement for interaction of PI3-kinase p110? with RAS in lung tumor maintenance.

Publications

Requirement for interaction of PI3-kinase p110α with RAS in lung tumor maintenance.

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