Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis

Ajiro, Masahiko; Nishidate, Toshihiko; Katagiri, Toyomasa; Nakamura, Yusuke

doi:10.3892/ijo_00000760

Cited by 9 publications

(3 citation statements)

References 40 publications

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“…Short hairpin RNA (shRNA)-mediated suppression of CNOT9 drastically suppresses the proliferation of breast cancer cells (Ajiro et al, 2009). In addition, CNOT9 forms a large complex consisting of Grb10, Grb10-interacting protein 1 (GIGYF1), GIGYF2, and Akt, all of which are components of epidermal growth factor receptor (EGFR) downstream signaling (Ajiro et al, 2010). The Akt phosphorylation that is induced by EGFR signaling is attenuated in the absence of CNOT9 (Ajiro et al, 2010), which suggests that CNOT9 enhances EGFR signaling and contributes to carcinogenesis and progression of cancer, particularly in mammary glands.…”

Section: Cnot9mentioning

confidence: 99%

Multifunctional roles of the mammalian CCR4â€“NOT complex in physiological phenomena

Shirai¹,

Suzuki²,

Morita³

et al. 2014

Front. Genet.

107

106

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The carbon catabolite repression 4 (CCR4)–negative on TATA-less (NOT) complex serves as one of the major deadenylases of eukaryotes. Although it was originally identified and characterized in yeast, recent studies have revealed that the CCR4–NOT complex also exerts important functions in mammals, -including humans. However, there are some differences in the composition and functions of the CCR4–NOT complex between mammals and yeast. It is noteworthy that each subunit of the CCR4–NOT complex has unique, multifunctional roles and is responsible for various physiological phenomena. This heterogeneity and versatility of the CCR4–NOT complex makes an overall understanding of this complex difficult. Here, we describe the functions of each subunit of the mammalian CCR4–NOT complex and discuss the molecular mechanisms by which it regulates homeostasis in mammals. Furthermore, a possible link between the disruption of the CCR4–NOT complex and various diseases will be discussed. Finally, we propose that the analysis of mice with each CCR4–NOT subunit knocked out is an effective strategy for clarifying its complicated functions and networks in mammals.

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Section: Cnot9mentioning

confidence: 99%

Multifunctional roles of the mammalian CCR4â€“NOT complex in physiological phenomena

Shirai¹,

Suzuki²,

Morita³

et al. 2014

Front. Genet.

107

106

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“…However, all the DE genes within our "B-other" group differed from class-defining genes of the so called "novel" ALL subtype introduced by Yeoh et al (3) implying that they specify a different subtype. Each validated gene in this category, i.e., CD3G, DFFA, GIGYF1, GIGYF2, and INTS3 were shown to play a role in neoplastic processes, including leukemia (41)(42)(43)(44)(45). However, none of these genes were published previously to be associated with pediatric BCP-ALL.…”

Section: Discussionmentioning

confidence: 97%

Coagulation FXIII-a Protein Expression Defines Three Novel Sub-Populations in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia Characterized By Distinct Gene Expression Signatures

Gyurina

Kárai

Újfalusi

et al. 2019

Blood

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Background Leukemic B-cell precursor (BCP) lymphoblasts were identified as a novel expression site for coagulation factor XIII subunit A (FXIII-A). FXIII-A expression determined by flow cytometry (FC) exhibited characteristically distinct expression patterns in subgroups of lymphoblasts. The FXIII-A negative subgroup was significantly associated with the 'B-other' genetic category and had an unfavorable disease outcome. Methods RNA was extracted from bone marrow lymphoblasts of 42 pediatric patients with BCP-acute lymphoblastic leukemia (ALL). FXIII-A expression was determined by multiparameter FC. Genetic diagnosis was based on conventional cytogenetic method and fluorescence in situ hybridization. Affymetrix GeneChip Human Primeview array was used to analyze global expression pattern of 28869 well-annotated genes. Microarray data were analyzed by Genespring GX14.9.1 software. Gene Ontology (GO) analysis was performed using Cytoscape 3.4.0 software with ClueGO application. Selected differentially expressed (DE) genes were validated by RT-Q-PCR. Results We demonstrated, for the first time, the general expression of F13A1 gene in pediatric BCP-ALL samples. The intensity of F13A1 expression corresponded to the expression of FXIII-A protein, as determined by FC. We observed three well-defined categories of FXIII-A protein expression: FXIII-A negative (<20% FXIII-A positive blasts), FXIII-A dim (20-80% FXIII-A positive blasts), and FXIII-A bright (>80% FXIII-A positive blasts). The intensity of the FXIII-A expression increased continuously, which excluded the existence of a distinct FXIII-A negative and a FXIII-A bright subpopulation within the FXIII-A dim subgroup (Image 1/A). These three subgroups defined three characteristic and distinct gene expression signatures detected by Affymetrix oligonucleotide microarrays. There were 26 DE genes found when comparing the FXIII-A negative with the FXIII-A bright subgroup. The FXIII-A dim vs. bright comparison resulted in 155 DE genes and there were 88 DE genes identified between the FXIII-A negative and dim subgroups (Image 1/B). Expression of F13A1 gene was detected and readily validated by RT-Q-PCR in every sample. Intensity of gene expression; however, was characteristically different among samples of the three different FXIII-A protein expression subgroups with an increasing intensity in terms of relative fold-changes measured by RT-Q-PCR from the FXIII-A negative, through dim to bright subgroups. We selected 13/45 genes based on fold-change results detected by microarray, whereas an additional 32/45 genes were selected according to enriched functional categories of potential interest as defined by the GO analysis. Relative gene expression intensity of ANGPTL2, EHMT1 FOXO1, HAP1, NUCKS1, NUP43, PIK3CG, RAPGEF5, SEMA6A, SPIN1, TRH, and WASF2, validated by RT-Q-PCR according to the FXIII-A status, followed the pattern of intensity of the expression of the F13A1 gene. Of these genes, ANGPTL2, EHMT1 FOXO1, HAP1, NUCKS1, PIK3CG, RAPGEF5, SEMA6A, SPIN1, TRH, and WASF2 appear to have a role in leukemia and other forms of cancer. NUP43 has not yet been shown to be associated with any forms of human cancer in contrast to other members of the NUP gene family. PLAC8 which is a trophoblast lineage marker was most intensively expressed in the FXIII-A dim subgroup. This gene has been shown to be aberrantly activated in various types of cancer arising in mammals and mammalian cancer cell lines, but not in any subtype of human ALL (Image 1/C). Gene expression signature of the FXIII-A negative subgroup showed an overlap with the signature of 'B-other' samples. We identified 14 DE genes by microarray overlapping with DE genes of the 'B-other' subgroup defined by the COALL Group. DFFA, GIGYF1, GIGYF2, and INTS3 were upregulated and CD3G was downregulated in the 'B-other' subgroup. Conclusions We described differential expression of genes not shown previously to be associated with pediatric BCP-ALL. Gene expression signature according to FXIII-A protein expression status defined three novel subgroups of pediatric BCP-ALL. Validated genes proved biologically and clinically relevant. Multiparameter FC appears to be an easy-to-use and affordable method to help in selecting FXIII-A negative patients who require a more elaborate and expensive molecular genetic investigation to design precision treatment. Figure Disclosures No relevant conflicts of interest to declare.

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“…The functional oncogenic role of CNOT9/RQCD1 in melanoma remains currently unknown although limited studies revealed RQCD1 implication in AKT activation and cell proliferation (Ajiro et al, 2009(Ajiro et al, , 2010. In particular, the CNOT9/RQCD1 mutant has demonstrated to stimulate stronger immune responses than the wild type, implicating the formation of a neoantigen that could be a potential therapeutic target although no drugs or clinical trials are available (Wong et al, 2015).…”

Section: Cnot9mentioning

confidence: 99%

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

Vanni

Tanda

Dalmasso

et al. 2020

Front. Mol. Biosci.

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Melanoma is one of the most aggressive tumors of the skin, and its incidence is growing worldwide. Historically considered a drug resistant disease, since 2011 the therapeutic landscape of melanoma has radically changed. Indeed, the improved knowledge of the immune system and its interactions with the tumor, and the ever more thorough molecular characterization of the disease, has allowed the development of immunotherapy on the one hand, and molecular target therapies on the other. The increased availability of more performing technologies like Next-Generation Sequencing (NGS), and the availability of increasingly large genetic panels, allows the identification of several potential therapeutic targets. In light of this, numerous clinical and preclinical trials are ongoing, to identify new molecular targets. Here, we review the landscape of mutated non-BRAF skin melanoma, in light of recent data deriving from Whole-Exome Sequencing (WES) or Whole-Genome Sequencing (WGS) studies on melanoma cohorts for which information on the mutation rate of each gene was available, for a total of 10 NGS studies and 992 samples, focusing on available, or in experimentation, targeted therapies beyond those targeting mutated BRAF. Namely, we describe 33 established and candidate driver genes altered with frequency greater than 1.5%, and the current status of targeted therapy for each gene. Only 1.1% of the samples showed no coding mutations, whereas 30% showed at least one mutation in the RAS genes (mostly NRAS) and 70% showed mutations outside of the RAS genes, suggesting potential new roads for targeted therapy. Ongoing clinical trials are available for 33.3% of the most frequently altered genes.

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Critical involvement of RQCD1 in the EGFR-Akt pathway in mammary carcinogenesis

Cited by 9 publications

References 40 publications

Multifunctional roles of the mammalian CCR4â€“NOT complex in physiological phenomena

Multifunctional roles of the mammalian CCR4â€“NOT complex in physiological phenomena

Coagulation FXIII-a Protein Expression Defines Three Novel Sub-Populations in Pediatric B-Cell Progenitor Acute Lymphoblastic Leukemia Characterized By Distinct Gene Expression Signatures

Non-BRAF Mutant Melanoma: Molecular Features and Therapeutical Implications

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