Genetic Validation of Cell Proliferation via Ras-Independent Activation of the Raf/Mek/Erk Pathway

Lechuga, Carmen G.; Simón-Carrasco, Lucía; Jacob, Harrys K.C.; Drosten, Matthias

doi:10.1007/978-1-4939-6424-6_20

Cited by 5 publications

(5 citation statements)

References 15 publications

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“…These observations illustrate that there are at least two independent mechanisms by which cells can proliferate in the absence of RAS proteins, loss of the p53/p21 Cip1 /Rb axis and increased KSR expression. Yet, in both cases, the presence of RAF proteins as well as their translocation to the plasma membrane are required [26,27,30], thus, indicating that RAF proteins are the key effectors of the MAPK pathway. Whether other regulatory events could induce the proliferation of MEFs in the absence of RAF proteins remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…Retroviral or lentiviral vectors were produced as described in 293T cells using the pCL-Eco packaging vector system or the ViraPower Lentiviral packaging mix (Thermo Fisher Scientific, Waltham, MA, USA), respectively [30]. pMSCV-KSR1-IRES-GFP (Addgene #25973; Watertown, MA, USA) and pMSCV-KSR2-IRES-GFP (Addgene #25969) were a gift from Rob Lewis [9].…”

Section: Plasmids and Viral Vector Productionmentioning

confidence: 99%

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KSR induces RAS‐independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors

et al. 2022

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The kinase suppressor of rat sarcoma (RAS) proteins (KSR1 and KSR2) have long been considered as scaffolding proteins required for optimal mitogen‐activated protein kinase (MAPK) pathway signalling. However, recent evidence suggests that they play a more complex role within this pathway. Here, we demonstrate that ectopic expression of KSR1 or KSR2 is sufficient to activate the MAPK pathway and to induce cell proliferation in the absence of RAS proteins. In contrast, the ectopic expression of KSR proteins is not sufficient to induce cell proliferation in the absence of either rapidly accelerated fibrosarcoma (RAF) or MAPK‐ERK kinase proteins, indicating that they act upstream of RAF. Indeed, KSR1 requires dimerization with at least one member of the RAF family to stimulate proliferation, an event that results in the translocation of the heterodimerized RAF protein to the cell membrane. Mutations in the conserved aspartic acid–phenylalanine–glycine motif of KSR1 that affect ATP binding impair the induction of cell proliferation. We also show that increased expression levels of KSR1 decrease the responsiveness to the KRASG12C inhibitor sotorasib in human cancer cell lines, thus suggesting that increased levels of expression of KSR may make tumour cells less dependent on KRAS oncogenic signalling.

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Section: Discussionmentioning

confidence: 99%

Section: Plasmids and Viral Vector Productionmentioning

confidence: 99%

KSR induces RAS‐independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors

et al. 2022

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“…These observations suggest that, at least in these fly tissues, Cic is the key mediator of Ras-driven cell proliferation. In contrast, inactivation of mammalian CIC in mouse embryonic fibroblasts lacking the three RAS isoforms, Hras, Nras and Kras, [45][46][47] failed to induce proliferation, indicating a more complex interpretation of RAS signaling in these mammalian cells [37]. In this regard, it has been shown that ERK proteins phosphorylate and inactivate additional repressors such as ERF or ETV6 (also known as TEL) [48,49].…”

Section: Role Of Cic In Ras-driven Proliferation In Mammalian Cellsmentioning

confidence: 99%

The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer

et al. 2018

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The transcriptional repressor Capicua (CIC) has emerged as an important rheostat of cell growth regulated by RAS/MAPK signaling. Cic was originally discovered in Drosophila, where it was shown to be inactivated by MAPK signaling downstream of the RTKs Torso and EGFR, which results in signal-dependent responses that are required for normal cell fate specification, proliferation and survival of developing and adult tissues. CIC is highly conserved in mammals, where it is also negatively regulated by MAPK signaling. Here, we review the roles of CIC during mammalian development, tissue homeostasis, tumor formation and therapy resistance. Available data indicate that CIC is involved in multiple biological processes, including lung development, liver homeostasis, autoimmunity and neurobehavioral processes. Moreover, CIC has been shown to be involved in tumor development as a tumor suppressor, both in human as well as in mouse models. Finally, several lines of evidence implicate CIC as a determinant of sensitivity to EGFR and MAPK pathway inhibitors, suggesting that CIC may play a broader role in human cancer than originally anticipated.

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“…Eight putative RGs were selected through functional enrichment analysis, all of which belonged to the ribosomal protein gene family except KARS . KARS is a member of the RAS protein family, which is mainly involved in cell proliferation [ 45 , 46 ]. KARS encodes both cytoplasmic and mitochondrial lysyl-tRNA synthetase, a moonlighting protein that has a typical function in protein synthesis [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Identification of Reference Genes for Reverse-Transcription Quantitative PCR in Goat Rumen

Zhao¹,

Cheng²,

Zhang³

et al. 2021

Animals

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As the largest chamber of the ruminant stomach, the rumen not only serves as the principal absorptive surface and nutrient transport pathway from the lumen into the animal, but also plays an important short-chain fatty acid (SCFA) metabolic role in addition to protective functions. Accurate characterization of the gene expression profiles of genes of interest is essential to the exploration of the intrinsic regulatory mechanisms of rumen development in goats. Thus, the selection of suitable reference genes (RGs) is an important prerequisite for real-time quantitative PCR (RT-qPCR). In the present study, 16 candidate RGs were identified from our previous transcriptome sequencing of caprine rumen tissues. The quantitative expressions of the candidate RGs were measured using the RT-qPCR method, and the expression stability of the RGs was assessed using the geNorm, NormFinder, and BestKeeper programs. GeNorm analysis showed that the M values were less than 0.5 for all the RGs except GAPT4, indicating that they were stably expressed in the rumen tissues throughout development. RPS4X and RPS6 were the two most stable RGs. Furthermore, the expressions of two randomly selected target genes (IGF1 and TOP2A), normalized by the selected most stable RGs (RPS4X and RPS6), were consistent with the results of RNA sequencing, while the use of GAPDH and ACTB as RGs resulted in altered profiles. Overall, RPS4X and RPS6 showed the highest expression stability and the lowest coefficients of variation, and could be used as the optimal reference combination for quantifying gene expression in rumen tissues via RT-qPCR analysis.

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Genetic Validation of Cell Proliferation via Ras-Independent Activation of the Raf/Mek/Erk Pathway

Cited by 5 publications

References 15 publications

KSR induces RAS‐independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors

KSR induces RAS‐independent MAPK pathway activation and modulates the efficacy of KRAS inhibitors

The Capicua tumor suppressor: a gatekeeper of Ras signaling in development and cancer

Genome-Wide Identification of Reference Genes for Reverse-Transcription Quantitative PCR in Goat Rumen

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