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?B-Ras proteins regulate both NF-?B-dependent inflammation and Ral-dependent proliferation.

ABSTRACT: The transformation of cells generally involves multiple genetic lesions that undermine control of both cell death and proliferation. We now report that ?B-Ras proteins act as regulators of NF-?B and Ral pathways, which control inflammation/cell death and proliferation, respectively. Cells lacking ?B-Ras therefore not only show increased NF-?B activity, which results in increased expression of inflammatory mediators, but also exhibit elevated Ral activity, which leads to enhanced anchorage-independent proliferation (AIP). ?B-Ras deficiency consequently leads to significantly increased tumor growth that can be dampened by inhibiting either Ral or NF-?B pathways, revealing the unique tumor-suppressive potential of ?B-Ras proteins. Remarkably, numerous human tumors show reduced levels of ?B-Ras, and increasing the level of ?B-Ras in these tumor cells impairs their ability to undergo AIP, thereby implicating ?B-Ras proteins in human disease.

SUBMITTER: Oeckinghaus A

PROVIDER: S-EPMC4177457 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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κB-Ras proteins regulate both NF-κB-dependent inflammation and Ral-dependent proliferation.

Oeckinghaus Andrea A Postler Thomas S TS Rao Ping P Schmitt Heike H Schmitt Verena V Grinberg-Bleyer Yenkel Y Kühn Lars I LI Gruber Christian W CW Lienhard Gustav E GE Ghosh Sankar S

Cell reports 20140915 6

The transformation of cells generally involves multiple genetic lesions that undermine control of both cell death and proliferation. We now report that κB-Ras proteins act as regulators of NF-κB and Ral pathways, which control inflammation/cell death and proliferation, respectively. Cells lacking κB-Ras therefore not only show increased NF-κB activity, which results in increased expression of inflammatory mediators, but also exhibit elevated Ral activity, which leads to enhanced anchorage-indepe ...[more]

PMID: 25220458

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Project description:Abstract: RAS-like (RAL) GTPases function in Wnt signalling-dependent intestinal stem cell proliferation and regeneration. Whether RAL proteins work as canonical RAS effectors in the intestine, and the mechanisms of how they contribute to tumorigenesis remain unclear. Here, we show that RAL GTPases are necessary and sufficient to activate EGFR/MAPK signalling in the intestine. We identify non-canonical roles of RAL GTPases not as RAS effectors, but rather by acting upstream of RAS activation via induction of EGFR internalisation . Knocking down Drosophila RalA from intestinal stem and progenitor cells leads to increased levels of plasma membrane-associated EGFR and decreased MAPK pathway activation. Importantly, in addition to impacting stem cell proliferation and damage-induced intestinal regeneration, this function of RAL GTPases drives EGFR-dependent tumorigenic growth in the intestine and in human mammary epithelium. Altogether, our results reveal previously unrecognised cellular and molecular contexts where RAL GTPases become essential mediators of EGFR-driven tissue homeostasis and malignant transformation. Results: RalA is required within ISCs to induce midgut adult midgut regeneration following damage by oral infection with Erwinia carotovora carotovora 15 (Ecc15) (Johansson et al., 2019). To achieve a global view of intestinal pathways affected by RalA, we performed a transcriptomic analysis by RNAseq of whole midguts from vehicle treated (Mock) or damaged (Ecc15 fed) control animals or following RalA knockdown in intestinal stem and progenitor cells using the escargot-gal4 driver (ISC/EB>) (Micchelli and Perrimon, 2006). Consistent with its effect on ISC proliferation (Johansson et al., 2019), RalA knockdown significantly impaired damage-induced upregulation of cell cycle genes in the midgut. Additionally, levels of multiple transcriptional targets of the EGFR/MAPK pathway (Golembo et al., 1996; Hsu et al., 2001; Jin et al., 2015; Meng and Biteau, 2015), such as argos (aos), rhomboid (rho), Sox21a and string (stg) were increased following Ecc15 infection in control midguts. The upregulation of these target genes was significantly impaired upon RalA knockdown.

Dataset Information

?B-Ras proteins regulate both NF-?B-dependent inflammation and Ral-dependent proliferation.

Publications

κB-Ras proteins regulate both NF-κB-dependent inflammation and Ral-dependent proliferation.

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