Nucleophosmin: from structure and function to disease development

Box, Joseph; Paquet, Nicolas; Adams, Mark N.; Boucher, Didier; Bolderson, Emma; O’Byrne, Kenneth J.; Richard, Derek J.

doi:10.1186/s12867-016-0073-9

Cited by 191 publications

(186 citation statements)

References 103 publications

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“…NPM1 is a nucleolar protein with diverse functions in the cell, including ribosome biogenesis, chromatin remodeling, and mRNA processing, in which it has been reported to function as a negative regulator of alternative splicing (45,46). We observed 11 NPM1 phosphopeptides that have also been identified in previous phosphoproteomic screens (47)(48)(49).…”

Section: Phosphoproteome Analysis Identifies a Role For Gsk-3 In Altesupporting

confidence: 54%

Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

Shinde¹,

Sidoli²,

Kulej³

et al. 2017

Journal of Biological Chemistry

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Edited by Eric R. FearonGlycogen synthase kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed protein kinase that regulates multiple signaling pathways. In vitro kinase assays and genetic and pharmacological manipulations of GSK-3 have identified more than 100 putative GSK-3 substrates in diverse cell types. Many more have been predicted on the basis of a recurrent GSK-3 consensus motif ((pS/pT)XXX(S/T)), but this prediction has not been tested by analyzing the GSK-3 phosphoproteome. Using stable isotope labeling of amino acids in culture (SILAC) and MS techniques to analyze the repertoire of GSK-3-dependent phosphorylation in mouse embryonic stem cells (ESCs), we found that ϳ2.4% of (pS/pT)XXX(S/T) sites are phosphorylated in a GSK-3-dependent manner. A comparison of WT and Gsk3a;Gsk3b knock-out (Gsk3 DKO) ESCs revealed prominent GSK-3-dependent phosphorylation of multiple splicing factors and regulators of RNA biosynthesis as well as proteins that regulate transcription, translation, and cell division. Gsk3 DKO reduced phosphorylation of the splicing factors RBM8A, SRSF9, and PSF as well as the nucleolar proteins NPM1 and PHF6, and recombinant GSK-3␤ phosphorylated these proteins in vitro. RNASeq of WT and Gsk3 DKO ESCs identified ϳ190 genes that are alternatively spliced in a GSK-3-dependent manner, supporting a broad role for GSK-3 in regulating alternative splicing. The MS data also identified posttranscriptional regulation of protein abundance by GSK-3, with ϳ47 proteins (1.4%) whose levels increased and ϳ78 (2.4%) whose levels decreased in the absence of GSK-3. This study provides the first unbiased analysis of the GSK-3 phosphoproteome and strong evidence that GSK-3 broadly regulates alternative splicing. Glycogen synthase kinase-3 (GSK-3)2 is a ubiquitously expressed, highly conserved serine/threonine kinase that plays a central role in multiple signaling pathways, most prominently as an antagonist of insulin/AKT and Wnt/␤-catenin signaling pathways (1). Unlike most protein kinases, GSK-3 is constitutively active and in general is inhibited by upstream signaling. GSK-3 was first identified as a protein kinase that phosphorylates and inhibits glycogen synthase, the rate-limiting enzyme in glycogen synthesis (2) and was later shown to antagonize canonical Wnt signaling (1). However, GSK-3 is now known to regulate a broad range of cellular processes, including cytoskeletal organization, circadian rhythm, cell growth and survival, immune responses, and developmental processes (1).In metazoans, GSK-3 is encoded by two similar genes, Gsk3a and Gsk3b, with 98% amino acid sequence identity in the catalytic domains of mammalian GSK-3␣ and GSK-3␤. The two genes are partially redundant, and mice with complete loss of Gsk3a are viable due to compensation by Gsk3b. However, Gsk3b loss-of-function mutations in mice are embryonic or neonatal lethal (3,4), and the Gsk3a;Gsk3b DKO is lethal in early embryogenesis (5, 6). Furthermore, DKO mouse ESCs maintain expression of pluripotency markers and are unab...

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Section: Phosphoproteome Analysis Identifies a Role For Gsk-3 In Altesupporting

confidence: 54%

Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

Shinde¹,

Sidoli²,

Kulej³

et al. 2017

Journal of Biological Chemistry

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“…In consideration of its multifunctional potentiality NPM1 can play roles both as a proto-oncogene and as a tumor suppressor [91,92]. In our tumor tissues we observed an average increase of 2.8 folds with respect to the non tumoral tissues.…”

Section: Nucleophosmin Npm (Npm1)mentioning

confidence: 59%

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

Pucci‐Minafra¹,

Cara²,

Musso³

et al. 2017

Preprint

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Abstract:The present investigation has been conducted on one hundred tissue fragments of breast cancer, collected and immediately cryopreserved following the surgical resection. The fragments were selected from patients with invasive ductal carcinoma of the breast, the most common and potentially aggressive type of mammary cancer, with the objective to increase the knowledge of breast cancer molecular markers, useful for diagnostic and prognostic categorization of patients, in assessing postsurgical therapeutic regimes. The proteomic screening, by 2D-IPG and mass spectrometry, allowed us to identify two main classes of protein clusters: proteins expressed ubiquitously at high levels in all patients, and proteins expressed sporadically among the same patients. Within the group of ubiquitous proteins, glycolytic enzymes and proteins with anti-apoptotic activity were predominant. Among the sporadic ones, proteins involved in cell motility, molecular chaperones and proteins involved in the detoxification appeared prevalent. The data of the present study indicates that the primary tumor growth is generally supported by two concurrent pathways: the inhibition of apoptosis and the stimulation of cellular proliferation. The second phase of the evolution of the tumor can be prematurely scheduled by the occasional presence of proteins involved in cell motility and in the defenses of the oxidative stress. To our knowledge this report on large-scales proteomics of breast cancer is currently a unique approach in the literature that offers the opportunity to evaluate the presence and recurrence of proteins to be used as prognostic indicators and susceptibility to metastasis in patients operated on for invasive ductal carcinoma of the breast.

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“…However, expression level of NPM and its cancerogenic function are not unequivocal and can differ in many types of cancers depending on a cell type, genetic context, or micro-environmental stimuli. Interestingly, expression of NPM at a transcription level can be converse to its expression at a translation level in the same type of cancer (Bonetti et al 2008; Box et al 2016; Leal et al 2014). NPM is overexpressed in many cancers, especially in highly malignant tumor subtypes (Li et al 2017; Sawazaki et al 2017).…”

Section: A Nucleolus As a Support Of Cancer Cellsmentioning

confidence: 99%

The nucleolus, an ally, and an enemy of cancer cells

Stępiński

2018

Histochem Cell Biol

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The rates of ribosome production by a nucleolus and of protein biosynthesis by ribosomes are tightly correlated with the rate of cell growth and proliferation. All these processes must be matched and appropriately regulated to provide optimal cell functioning. Deregulation of certain factors, including oncogenes, controlling these processes, especially ribosome biosynthesis, can lead to cell transformation. Cancer cells are characterized by intense ribosome biosynthesis which is advantageous for their growth and proliferation. On the other hand, this feature can be engaged as an anticancer strategy. Numerous nucleolar factors such as nucleolar and ribosomal proteins as well as different RNAs, in addition to their role in ribosome biosynthesis, have other functions, including those associated with cancer biology. Some of them can contribute to cell transformation and cancer development. Others, under stress evoked by different factors which often hamper function of nucleoli and thus induce nucleolar/ribosomal stress, can participate in combating cancer cells. In this sense, intentional application of therapeutic agents affecting ribosome biosynthesis can cause either release of these molecules from nucleoli or their de novo biosynthesis to mediate the activation of pathways leading to elimination of harmful cells. This review underlines the role of a nucleolus not only as a ribosome constituting apparatus but also as a hub of both positive and negative control of cancer development. The article is mainly based on original papers concerning mechanisms in which the nucleolus is implicated directly or indirectly in processes associated with neoplasia.

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Nucleophosmin: from structure and function to disease development

Cited by 191 publications

References 103 publications

Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

Phosphoproteomics reveals that glycogen synthase kinase-3 phosphorylates multiple splicing factors and is associated with alternative splicing

Retrospective Proteomic Screening of 100 Breast Cancer Tissues

The nucleolus, an ally, and an enemy of cancer cells

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