RAS proteins are small GTPases known for their involvement in oncogenesis: around 25% of human tumors present mutations in a member of this family. RAS operates in a complex signaling network with multiple activators and effectors, which allows them to regulate many cellular functions such as cell proliferation, differentiation, apoptosis, and senescence. Phosphatidylinositol 3-kinase (PI3K) is one of the main effector pathways of RAS, regulating cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. However, it is the involvement of this pathway in human tumors that has attracted most attention. PI3K has proven to be necessary for RAS-induced transformation in vitro, and more importantly, mice with mutations in the PI3K catalytic subunit p110α that block its ability to interact with RAS are highly resistant to endogenous oncogenic KRASinduced lung tumorigenesis and HRAS-induced skin carcinogenesis. These animals also have a delayed development of the lymphatic vasculature. Many PI3K inhibitors have been developed that are now in clinical trials. However, it is a complex pathway with many feedback loops, and interactions with other pathways make the results of its inhibition hard to predict. Combined therapy with another RAS-regulated pathway such as RAF/MEK/ ERK may be the most effective way to treat cancer, at least in animal models mimicking the human disease. In this review, we will summarize current knowledge about how RAS regulates one of its best-known effectors, PI3K.
We have used mouse embryonic fibroblasts (MEFs) devoid of Ras proteins to illustrate that they are essential for proliferation and migration, but not for survival, at least in these cells. These properties are unique to the Ras subfamily of proteins because ectopic expression of other Ras-like small GTPases, even when constitutively active, could not compensate for the absence of Ras proteins. Only constitutive activation of components of the Raf/Mek/Erk pathway was sufficient to sustain normal proliferation and migration of MEFs devoid of Ras proteins. Activation of the phosphatidylinositol 3-kinase (PI3K)/PTEN/Akt and Ral guanine exchange factor (RalGEF)/Ral pathways, either alone or in combination, failed to induce proliferation or migration of Rasless cells, although they cooperated with Raf/Mek/Erk signalling to reproduce the full response mediated by Ras signalling. In contrast to current hypotheses, Ras signalling did not induce proliferation by inducing expression of D-type Cyclins. Rasless MEFs had normal levels of Cyclin D1/Cdk4 and Cyclin E/Cdk2. However, these complexes were inactive. Inactivation of the pocket proteins or knock down of pRb relieved MEFs from their dependence on Ras signalling to proliferate.
H-ras, N-ras, and K-ras are canonical ras gene family members frequently activated by point mutation in human cancers and coding for 4 different, highly related protein isoforms (H-Ras, N-Ras, K-Ras4A, and K-Ras4B). Their expression is nearly ubiquitous and broadly conserved across eukaryotic species, although there are quantitative and qualitative differences of expression depending on the tissue and/or developmental stage under consideration. Extensive functional studies have determined during the last quarter century that these Ras gene products are critical components of signaling pathways that control eukaryotic cell proliferation, survival, and differentiation. However, because of their homology and frequent coexpression in various cellular contexts, it remained unclear whether the different Ras proteins play specific or overlapping functional roles in physiological and pathological processes. Initially, their high degree of sequence homology and the observation that all Ras isoforms share common sets of downstream effectors and upstream activators suggested that they were mostly redundant functionally. In contrast, the notion of functional specificity for each of the different Ras isoforms is supported at present by an increasing body of experimental observations, including 1) the fact that different ras isoforms are preferentially mutated in specific types of tumors or developmental disorders; 2) the different transforming potential of transfected ras genes in different cell contexts; 3) the distinct sensitivities exhibited by the various Ras family members for modulation by different GAPs or GEFs; 4) the demonstration that different Ras isoforms follow distinct intracellular processing pathways and localize to different membrane microdomains or subcellular compartments; 5) the different phenotypes displayed by genetically modified animal strains for each of the 3 ras loci; and 6) the specific transcriptional networks controlled by each isoform in different cellular settings.
SummaryRAS 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 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 p110α expression or activity has comparable effects, albeit with greater toxicities.
Multiple myeloma (MM) is a hematologic cancer characterized by clonal proliferation of plasma cells in the bone marrow (BM). The progression, from the early stages of the disease as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM and occasionally extramedullary disease, is drastically affected by the tumor microenvironment (TME). Soluble factors and direct cell–cell interactions regulate MM plasma cell trafficking and homing to the BM niche. Mesenchymal stromal cells, osteoclasts, osteoblasts, myeloid and lymphoid cells present in the BM create a unique milieu that favors MM plasma cell immune evasion and promotes disease progression. Moreover, TME is implicated in malignant cell protection against anti-tumor therapy. This review describes the main cellular and non-cellular components located in the BM, which condition the immunosuppressive environment and lead the MM establishment and progression.
Ras proteins are key regulators of signalling cascades, controlling many processes such as proliferation, differentiation and apoptosis. Mutations in these proteins or in their effectors, activators and regulators are associated with pathological conditions, particularly the development of various forms of human cancer. RAS proteins signal through direct interaction with a number of effector enzymes, one of the best characterized being type I phosphatidylinositol (PI) 3-kinases. Although the ability of RAS to control PI 3-kinase has long been well established in cultured cells, evidence for a role of the interaction of endogenous RAS with PI 3-kinase in normal and malignant cell growth in vivo has only been obtained recently. Mice with mutations in the PI 3-kinase catalytic p110a isoform that block its ability to interact with RAS are highly resistant to endogenous KRAS oncogene induced lung tumourigenesis and HRAS oncogene induced skin carcinogenesis. Cells from these mice show proliferative defects and selective disruption of signalling from certain growth factors to PI 3-kinase, while the mice also display delayed development of the lymphatic vasculature. The interaction of RAS with p110a is thus required in vivo for some normal growth factor signalling and also for RAS-driven tumour formation. RAS family members were among the first oncogenes identified over 40 years ago. In the late 1960s, the rat-derived Harvey and Kirsten murine sarcoma retroviruses were discovered and subsequently shown to promote cancer formation through related oncogenes, termed RAS (from rat sarcoma virus). The central role of RAS proteins in human cancer is highlighted by the large number of tumours in which they are activated by mutation: approximately 20% of human cancers carry a mutation in RAS proteins. Because of the complex signalling network in which RAS operates, with multiple activators and effectors, each with a different pattern of tissue-specific expression and a distinct set of intracellular functions, one of the critical issues concerns the specific role of each effector in RAS-driven oncogenesis. In this chapter, we summarize current knowledge about how RAS regulates one of its best-known effectors, phosphoinositide 3-kinase (PI3K).
We characterized differential gene expression profiles of fibroblast cell lines harboring single or double-homozygous null mutations in H-ras and N-ras. Whereas the expression level of the individual H-, N-and K-ras genes appeared unaffected by the presence or absence of the other ras loci, significant differences were observed between the expression profiles of cells missing N-ras and/or H-ras. Absence of N-ras produced much stronger effects than absence of H-ras over the profile of the cellular transcriptome. N-ras À/À and H-ras À/À fibroblasts displayed rather antagonistic expression profiles and the transcriptome of H-ras À/À cells was significantly closer to that of wild-type fibroblasts than to that of N-ras À/À cells. Classifying all differentially expressed genes into functional categories suggested specific roles for H-Ras and N-Ras. It was particularly striking in N-ras À/À cells the upregulation of a remarkable number of immunity-related genes, as well as of several loci involved in apoptosis. Reverse-phase protein array assays demonstrated in the same N-ras À/À cells the overexpression and nuclear migration of tyrosine phosphorylated signal transducer and activator of transcription 1 (Stat1) which was concomitant with transcriptional activation mediated by interferon-stimulated response elements. Significantly enhanced numbers of apoptotic cells were also detected in cultures of N-ras À/À cells. Our data support the notion that different Ras isoforms play functionally distinct cellular roles and indicate that N-Ras is significantly involved in immune modulation/host defense and apoptotic responses. Oncogene (2007) 26, 917-933.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.