Nucleophosmin, a multifunctional nucleolar organizer with a role in DNA repair

López, David J.; Rodríguez, José Antonio; Bañuelos, Sonia

doi:10.1016/j.bbapap.2020.140532

Cited by 34 publications

(30 citation statements)

References 143 publications

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“…NPM1 is a highly conserved protein commonly found in eukaryotic cells. It is mainly localized in the nucleus and can shuttle between the nucleus and cytoplasm to participate in nucleocytoplasmic signal transport (3,4). Studies have shown that the content of NPM1 in tumor cells and growing cells is significantly higher than that in quiescent cells (36,37).…”

Section: Discussionmentioning

confidence: 99%

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NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

et al. 2021

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BackgroundOverexpression of NPM1 can promote the growth and proliferation of various tumor cells. However, there are few studies on the comprehensive analysis of NPM1 in lung adenocarcinoma (LUAD).MethodsTCGA and GEO data sets were used to analyze the expression of NPM1 in LUAD and clinicopathological analysis. The GO/KEGG enrichment analysis of NPM1 co-expression and gene set enrichment analysis (GSEA) were performed using R software package. The relationship between NPM1 expression and LUAD immune infiltration was analyzed using TIMER, GEPIA database and TCGA data sets, and the relationship between NPM1 expression level and LUAD m6A modification and glycolysis was analyzed using TCGA and GEO data sets.ResultsNPM1 was overexpressed in a variety of tumors including LUAD, and the ROC curve showed that NPM1 had a certain accuracy in predicting the outcome of tumors and normal samples. The expression level of NPM1 in LUAD is significantly related to tumor stage and prognosis. The GO/KEGG enrichment analysis indicated that NPM1 was closely related to translational initiation, ribosome, structural constituent of ribosome, ribosome, Parkinson disease, and RNA transport. GSEA showed that the main enrichment pathway of NPM1-related differential genes was mainly related to mTORC1 mediated signaling, p53 hypoxia pathway, signaling by EGFR in cancer, antigen activates B cell receptor BCR leading to generation of second messengers, aerobic glycolysis and methylation pathways. The analysis of TIMER, GEPIA database and TCGA data sets showed that the expression level of NPM1 was negatively correlated with B cells and NK cells. The TCGA and GEO data sets analysis indicated that the NPM1 expression was significantly correlated with one m6A modifier related gene (YTHDF2) and five glycolysis related genes (ENO1, HK2, LDHA, LDHB and SLC2A1).ConclusionNPM1 is a prognostic biomarker involved in immune infiltration of LUAD and associated with m6A modification and glycolysis. NPM1 can be used as an effective target for diagnosis and treatment of LUAD.

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Section: Discussionmentioning

confidence: 99%

“…Nucleophosmin 1 (NPM1) is a multifunctional protein that is mainly localized in nucleoli and shuttles between the nucleus and cytoplasm (3). In recent years, the focus of NPM1 research has gradually shifted from hematological diseases to solid tumors (4,5).…”

Section: Introductionmentioning

confidence: 99%

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

et al. 2021

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“…The ability of APE1 to bind and process RNA seems to be empowered by the disordered N-terminus of this protein, which is thought to be a recent evolutionary acquisition in mammals and it is found to be highly conserved in mammals, possibly constituting an important gain of function example [61]. This domain, in fact, was found to be essential for APE1 recruitment to nuclear subcompartments, including the nucleolus [62], and for its interaction with other BER factors [63] and other partners like NPM1 [61], which, in recent years, have also been linked to several novel functions including LLPS [64].…”

Section: The Apurinic/apyrimidinic Endonuclease (Ape1) Is a Crucial Bmentioning

confidence: 99%

Role of phase partitioning in coordinating DNA damage response: focus on the Apurinic Apyrimidinic Endonuclease 1 interactome

Antoniali

Dalla

et al. 2020

Biomolecular Concepts

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Liquid-liquid phase separation (LLPS) is a way to concentrate biochemical reactions while excluding noninteracting components. Disordered domains of proteins, as well as interaction with RNA, favor condensation but are not mandatory for modulating this process. Recent insights about phase-separation mechanisms pointed to new fascinating models that could explain how cells could cope with DNA damage responses, conferring both spatial and temporal fine regulation. APE1 is a multifunctional protein belonging to the Base Excision Repair (BER) pathway, bearing additional ‘non-canonical’ DNA-repair functions associated with processes like RNA metabolism. Recently, it has been highlighted that several DNA repair enzymes, such as 53BP1 and APE1, are endowed with RNA binding abilities. In this work, after reviewing the recent literature supporting a role of LLPS in DDR, we analyze, as a proof of principle, the interactome of APE1 using a bioinformatics approach to look for clues of LLPS in BER. Some of the APE1 interactors are associated with cellular processes in which LLPS has been either proved or proposed and are involved in different pathogenic events. This work might represent a paradigmatical pipeline for evaluating the relevance of LLPS in DDR.

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“…Previous studies adduced a wealth of evidence to support the correlation between the expression of NPM1 and c-Myc [13]. NPM1 binds the c-myc gene promoter, resulting in transcriptional regulation of the c-myc gene [37]. In addition, the endogenous and exogenous NPM1 protein has the ability to directly interact with the c-Myc protein to regulate the expression of c-Myc target genes at the promoter [38].…”

Section: Discussionmentioning

confidence: 99%

Proteomic Profiling of BRAFV600E Mutant Colon Cancer Cells Reveals the Involvement of Nucleophosmin/c-Myc Axis in Modulating the Response and Resistance to BRAF Inhibition by Vemurafenib

Grbčić

Čupić

Gamberi

et al. 2021

IJMS

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BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.

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Nucleophosmin, a multifunctional nucleolar organizer with a role in DNA repair

Cited by 34 publications

References 143 publications

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

NPM1 Is a Prognostic Biomarker Involved in Immune Infiltration of Lung Adenocarcinoma and Associated With m6A Modification and Glycolysis

Role of phase partitioning in coordinating DNA damage response: focus on the Apurinic Apyrimidinic Endonuclease 1 interactome

Proteomic Profiling of BRAFV600E Mutant Colon Cancer Cells Reveals the Involvement of Nucleophosmin/c-Myc Axis in Modulating the Response and Resistance to BRAF Inhibition by Vemurafenib

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