c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma

Blasco, Rafael; Francoz, Sarah; Santamarı́a, David; Cañamero, Marta; Dubus, Pierre; Charron, Jean; Baccarini, Manuela; Barbacid, Mariano

doi:10.1016/j.ccr.2011.04.002

Cited by 267 publications

(285 citation statements)

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“…Experimental evidence supporting the role of this gene in lung cancer comes from transgenic mice expressing mutated K-ras, in which atypical adenomatous hyperplasia and AdenoCa develop (16,17). In these models, high expression of oncogenic RAS promotes carcinogenesis through a signaling pathway that critically depends on c-RAF (45) and NF-κB (21,46). In vitro analyses based on RNAi screens also point to NF-κB and the atypical IκB kinase family member TBK1 as positive regulators of survival and tumorigenicity of human lung cancer cells bearing mutated K-ras (29).…”

Section: Discussionmentioning

confidence: 99%

TPL2 kinase is a suppressor of lung carcinogenesis

Gkirtzimanaki

Gkouskou

Oleksiewicz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Lung cancer is a heterogeneous disease at both clinical and molecular levels, posing conceptual and practical bottlenecks in defining key pathways affecting its initiation and progression. Molecules with a central role in lung carcinogenesis are likely to be targeted by multiple deregulated pathways and may have prognostic, predictive, and/or therapeutic value. Here, we report that Tumor Progression Locus 2 (TPL2), a kinase implicated in the regulation of innate and adaptive immune responses, fulfils a role as a suppressor of lung carcinogenesis and is subject to diverse genetic and epigenetic aberrations in lung cancer patients. We show that allelic imbalance at the TPL2 locus, up-regulation of microRNA-370, which targets TPL2 transcripts, and activated RAS (rat sarcoma) signaling may result in down-regulation of TPL2 expression. Low TPL2 levels correlate with reduced lung cancer patient survival and accelerated onset and multiplicity of urethane-induced lung tumors in mice. Mechanistically, TPL2 was found to antagonize oncogene-induced cell transformation and survival through a pathway involving p53 downstream of cJun N-terminal kinase (JNK) and be required for optimal p53 response to genotoxic stress. These results identify multiple oncogenic pathways leading to TPL2 deregulation and highlight its major tumor-suppressing function in the lung.

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Section: Discussionmentioning

confidence: 99%

TPL2 kinase is a suppressor of lung carcinogenesis

Gkirtzimanaki

Gkouskou

Oleksiewicz

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Cells lacking Erk1 and Erk2 share many features of Rasless cells, including cell cycle arrest in G1 (3,6). Indeed, ablation of these kinases in adult mice induced rapid wasting of mice in a fashion highly reminiscent of mice lacking Ras proteins (7). Hence, we expected that ablation of Erk kinases would also lead to p53-mediated cell cycle arrest.…”

Section: G1 Arrest S/g2/m S/g2/m G1mentioning

confidence: 99%

“…Hence, we expected that ablation of Erk kinases would also lead to p53-mediated cell cycle arrest. To test this hypothesis, we generated Erkless (Erk1 −/− ;Erk2 −/− ) cells by ectopic expression of a Cre recombinase in Erklox (Erk1 −/− ;Erk2 lox/lox ) cells (7). As shown in Fig.…”

Section: G1 Arrest S/g2/m S/g2/m G1mentioning

confidence: 99%

Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway

Drosten

Sum

Lechuga

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The Ras family of small GTPases constitutes a central node in the transmission of mitogenic stimuli to the cell cycle machinery. The ultimate receptor of these mitogenic signals is the retinoblastoma (Rb) family of pocket proteins, whose inactivation is a required step to license cell proliferation. However, little is known regarding the molecular events that connect Ras signaling with the cell cycle. Here, we provide genetic evidence to illustrate that the p53/ p21 Cdk-interacting protein 1 (Cip1)/Rb axis is an essential component of the Ras signaling pathway. Indeed, knockdown of p53, p21Cip1, or Rb restores proliferative properties in cells arrested by ablation of the three Ras loci, H-, N-and K-Ras. Ras signaling selectively inactivates p53-mediated induction of p21Cip1 expression by inhibiting acetylation of specific lysine residues in the p53 DNA binding domain. Proliferation of cells lacking both Ras proteins and p53 can be prevented by reexpression of the human p53 ortholog, provided that it retains an active DNA binding domain and an intact lysine residue at position 164. These results unveil a previously unidentified role for p53 in preventing cell proliferation under unfavorable mitogenic conditions. Moreover, we provide evidence that cells lacking Ras and p53 proteins owe their proliferative properties to the unexpected retroactivation of the Raf/Mek/Erk cascade by a Ras-independent mechanism.T he RAS genes have been extensively studied due to their key role in mediating mitogenic signaling as well as their high prevalence in human cancers, including those cancers with poor survival rates, such as lung adenocarcinoma, colorectal carcinoma, and pancreatic ductal adenocarcinoma (1, 2). However, the mechanisms by which Ras proteins mediate mitogenic signaling in either normal or tumor cells remain obscure, especially beyond activation of the Raf/Mek/Erk cascade. Recent genetic studies have underscored the relevance of Ras proteins in cellular homeostasis by demonstrating that cells lacking the three Ras loci, H-Ras, N-Ras, and K-Ras (Rasless cells), are completely unable to proliferate (3, 4). Indeed, systemic ablation of these loci in adult mice causes rapid deterioration of multiple tissues, leading to their death in a few days.GTP-loaded Ras proteins promote activation of various downstream signal transduction pathways, mainly the Raf/Mek/Erk kinase cascade, the PI3K/Akt route, and the Ral guanine dissociation stimulator (RalGDS) pathway (1). Activation of other pathways, such as those pathways driven by the Rac family of small G proteins and phospholipase C, has also been illustrated (1). However, genetic interrogation of the pathways essential for cell proliferation has illustrated that only constitutive activation of the Raf, Mek, or Erk kinase can bypass the requirement for Ras proteins to sustain cell division, at least in vitro (3, 4). Indeed, constitutive activation of the PI3K/Akt and RalGDS pathways was incapable of inducing cell proliferation in the absence of Ras proteins. In agreement wit...

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“…RAS and several of its downstream effectors, including BRAF, have been shown to be commonly mutated in broad range of human cancers. [16][17][18][19] With the identification of RAS mutation as a strong predictor of clinical resistance to epidermal growth factor receptor (EGFR)-targeted therapies, RAS mutational testing has been incorporated into the routine clinical care of patients with colorectal and lung cancers. 15 It becomes obvious that determining the molecular and viral profiling in lung cancer patients would be a cardinal next step in order to control this lethal disease.…”

Section: Dear Editormentioning

confidence: 99%

Molecular pathological findings of Merkel cell polyomavirus in lung cancer: A possible etiopathogenetic link?

Αντωνίου

Lasithiotaki

Symvoulakis

et al. 2013

Intl Journal of Cancer

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The proportion of cancers caused by infectious agents, including bacteria, parasitic worms and viruses, was recently estimated to be more than 20%, 1,2 while the contribution of several viruses is particularly high in certain types of cancer. 3Over 50 years of polyomavirus research has provided novel insights into not only the general biological functions in mammalian cells but has also provided a great deal of information as to how conditions can be altered and signaling systems tweaked to produce transformation phenotypes. [4][5][6] Over the past few years, three new members (KIV, WUV and MCPyV) have joined the two previously known (JCV and BKV) human polyomaviruses. [4][5][6] MCPyV was the third novel polyomavirus identified in a rare but aggressive skin cancer of neuroendocrine origin, termed Merkel cell carcinoma. 7 We appreciate the comments of the Japanese research group (submitted letter IJC-13-0568), giving us the opportunity to further discuss the role of polyoma viruses, and particularly that of Merkel virus, in lung carcinogenesis, as a number of studies have recently been published in this interesting research field. [8][9][10][11] Polyoma viruses, such as BK virus (BKV), JC virus (JCV) and MCPyV are typically non-oncogenic. The evidence for their role in human cancer remains controversial, although they have been detected in a variety of human neoplasms. 2The aforementioned viruses BKV, JCV and SV40, or their early proteins can induce tumors in animal models, and can immortalize or transform cultured cells, including human cells. 4,12 However, similar studies on the newly discovered polyoma viruses are lacking.We have read with great interest the commentary by Hashida et al (submitted letter IJC-13-0568), as the authors have shown for the first time in their original study, a prevalence of 17.9% for MCPyV in non-small cell lung cancer (NSCLC) in an Asian population. The current literature in lung cancinogenesis and more specifically in NSCLC has detected a varying prevalence for MCPyV from 5% in Chile, 11 9.1% in Greece 8 to 16.7% in North America. 10 It should also be noted that both HPV and MCPyV are directly associated with 33% of NSCLC cases. Moreover, our preliminary data indicate that in the same set of samples, 8 HPV DNA is detectable in 19% of the specimens (unpublished data).We are of the opinion that these variations in prevalence between studies from different geographical regions emphasize the complexity of regulation levels at different stages in carcinogenesis. Recently, the interplay of the microenvironment, pathogens, immunity, inflammation, cellular epigenetic alterations and various chronic diseases has attracted increasing attention.12-14 Previous studies thus far have shown that factors, such as disease stage, clinical parameters and methodological issues are rather minor issues. It is becoming more evident that further studies are required to determine whether polyomavirus may be placed among the determinants of risk.Smoking is a major risk factor for lung cancer and it is reco...

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c-Raf, but Not B-Raf, Is Essential for Development of K-Ras Oncogene-Driven Non-Small Cell Lung Carcinoma

Cited by 267 publications

References 50 publications

TPL2 kinase is a suppressor of lung carcinogenesis

TPL2 kinase is a suppressor of lung carcinogenesis

Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway

Molecular pathological findings of Merkel cell polyomavirus in lung cancer: A possible etiopathogenetic link?

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