Protein mislocalization: Mechanisms, functions and clinical applications in cancer

Wang, Xiaohong; Li, Shulin

doi:10.1016/j.bbcan.2014.03.006

Cited by 62 publications

(59 citation statements)

References 185 publications

(182 reference statements)

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“…For many proteins, cellular mislocalization interferes with their functions and can induce tumor development and metastasis ; in AML, several mutations of the exon 12 of NPM1 led to its cytoplasmatic localization .…”

Section: Discussionmentioning

confidence: 99%

“…For many proteins, cellular mislocalization interferes with their functions and can induce tumor development and metastasis [36]; in AML, several mutations of the exon 12 of NPM1 led to its cytoplasmatic localization [11]. Nucleophosmin 1 exerts its major cellular functions as an oligomer [37,38], thus it is of crucial interest to investigate potential different ways of oligomerization and a possible link of oligomeric states of the protein to leukomogenicity of mutations in the CTD.…”

Section: Discussionmentioning

confidence: 99%

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The acute myeloid leukemia‐associated Nucleophosmin 1 gene mutations dictate amyloidogenicity of the C‐terminal domain

et al. 2019

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Nucleophosmin 1 (NPM1) is a nucleus‐cytoplasm shuttling protein ubiquitously expressed and highly conserved. It is involved in many cellular processes and its gene is mutated in ~ 50–60% of Acute Myeloid Leukemia (AML) patients. These mutations cause its cytoplasmic mislocation and accumulation (referred to as NPM1c+) and open the door to rational targeted therapy for AML diseases with mutated NPM1. Currently, there is limited knowledge on the mechanism of action of NPM1c+ and on structural determinants of the leukemogenic potential of AML mutations. Numerous previous studies outlined an unexpected amyloid‐like aggregation tendency of several regions located in the C‐terminal domain that, in wild‐type form, fold as a three‐helical‐bundle. Here, using a combination of different techniques including Thioflavin T fluorescence, congo red absorbance, CD spectroscopy, Scanning Electron Microscopy (SEM) and wide‐angle X‐ray scattering on a series of peptides bearing mutations, we evidence that the amyloidogenicity of NPM1 mutants is directly linked to AML. Noticeably, AML point mutations strongly affect the amyloid cytotoxic effects in neuroblastoma cells and the morphologies of deriving fibrils. This study paves the way to deepen our understanding of AML‐associated NPM1 mutants, and could help to break new ground for the identification of novel drugs targeting NPM1c+ for treatment of AML.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The acute myeloid leukemia‐associated Nucleophosmin 1 gene mutations dictate amyloidogenicity of the C‐terminal domain

et al. 2019

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“…All revealed discrepancies between Pv11 and other cells are potential examples of protein mislocalization (Table 1), because localization in Pv11 cells was stricter than in other cells. Such protein mislocalization can be detrimental because it occurs in many cancers (23).…”

Section: Discussionmentioning

confidence: 99%

“…Thus, differences in PvLEA nuclear transport between different cells can be simply accounted by differences in structure of these nuclear-trafficking proteins. Differences in importins’ regulation and expression can be also a source of protein mislocalization (23).…”

Section: Discussionmentioning

confidence: 99%

Intracellular localization and gene expression analysis provide new insights on LEA proteins’ diversity in anhydrobiotic midge

Несмелов

et al. 2019

Preprint

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20Anhydrobiosis, an adaptive ability to withstand complete desiccation, is in insects 21 limited to a single species: the nonbiting midge Polypedilum vanderplanki (the sleeping 22 chironomid). Evolution of anhydrobiosis in a single representative of a large genus is 23 associated with drastic changes in genome structure, including the emergence of new 24 multimember gene families directly involved in desiccation tolerance. Among them, Late 25 Embryogenesis Abundant (LEA) proteins, which protect other proteins from aggregation 26 caused by desiccation, are believed to originate via horizontal gene transfer from a bacterial 27 donor. To obtain new insights on the biological background of the expanded 27-member LEA 28 protein group in P. vanderplanki, we investigated the expression of corresponding genes in a 29 P. vanderplanki-derived cell line, capable of anhydrobiosis, in a normal state and during 30 induction of desiccation tolerance. We found that all LEA proteins genes identified in P.31 vanderplanki's genome except PvLea16 and PvLea17 are also expressed in Pv11 cells. Their 32 expression was elevated in response to anhydrobiosis-inducing trehalose treatment. 33 Expression patterns of PvLea genes were well preserved in Pv11 cells in comparison to P. 34 vanderplanki's larvae both in the control group and during the anhydrobiosis cycle. We also 35 investigated localization of LEA proteins in Pv11 cells and Sf9 cells and found a different 36 level of conservation in intracellular localization of the protein expressed in mammalian and 37 insect cells. 38 39 Introduction 40 One of the most intriguing adaptations to extreme environments is the phenomenon of 41 anhydrobiosis-the ability to withstand complete desiccation in a nonmetabolic state (see 42 review in (1)-which allows living organisms to revive after complete desiccation. 3 43 Organisms capable of entering anhydrobiosis are found across different taxa, and the larvae 44 of the chironomid Polypedilum vanderplanki (Insecta, Diptera) are one of the most complex 45 of these from an evolutionary point of view, as well as being a unique case of emergence of 46 anhydrobiosis in a single species of eukaryotes (2). 47 For the larvae, entering the anhydrobiotic state takes 48 hours and is mediated by 48 several key events including replacement of water with trehalose and vitrification, as well as 49 accumulation of protective biomolecules, including heat shock proteins, antioxidants and 50 enzymes, aquaporins, and Late Embryogenesis Abundant (LEA) proteins (2,3). The latter are 51 highly hydrophilic proteins, well known for their protective effect against water deficits, and 52 they are found in anhydrobiotic organisms in both the plant and animal kingdoms (2). 53 Previously, we identified 27 genes of LEA proteins (PvLea) in the P. vanderplanki 54 genome, all of which are encoding members of LEA group 3. Many of these genes become 55 induced during desiccation in larvae (4). LEA proteins are believed to be one of the main 56 participants in anhydrobiosis mechanisms, ...

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“…1 Mislocalisation and miscompartmentalisation may be detrimental for cells and organisms and have been associated with human diseases. 1,2 The eukaryotic cell nucleus contains many different compartments and most nuclear events do not occur uniformly throughout the nucleus. Such events are typically limited to specific, spatially defined sites.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the nuclear matrix targeting sequence (NMTS) of the BPV1 E8/E2 protein — the shortest known NMTS

Sankovski

Karro²,

Sepp

et al. 2015

Nucleus

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Technological advantages in sequencing and proteomics have revealed the remarkable diversity of alternative protein isoforms. Typically, the localization and functions of these isoforms are unknown and cannot be predicted. Also the localization signals leading to particular subnuclear compartments have not been identified and thus, predicting alternative functions due to alternative subnuclear localization is limited only to very few subnuclear compartments. Knowledge of the localization and function of alternative protein isoforms allows for a greater understanding of cellular complexity. In this article, we characterize a short and well-defined signal targeting the bovine papillomavirus type 1 E8/E2 protein to the nuclear matrix. The targeting signal comprises the peptide coded by E8 ORF, which is spliced together with part of the E2 ORF to generate the E8/E2 mRNA. Localization to the nuclear matrix correlates well with the transcription repression activities of E8/E2; a single point mutation directs the E8/E2 protein into the nucleoplasm, and transcription repression activity is lost. Our data prove that adding as few as~10 amino acids by alternative transcription/alternative splicing drastically alters the function and subnuclear localization of proteins. To our knowledge, E8 is the shortest known nuclear matrix targeting signal.

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Protein mislocalization: Mechanisms, functions and clinical applications in cancer

Cited by 62 publications

References 185 publications

The acute myeloid leukemia‐associated Nucleophosmin 1 gene mutations dictate amyloidogenicity of the C‐terminal domain

The acute myeloid leukemia‐associated Nucleophosmin 1 gene mutations dictate amyloidogenicity of the C‐terminal domain

Intracellular localization and gene expression analysis provide new insights on LEA proteins’ diversity in anhydrobiotic midge

Characterization of the nuclear matrix targeting sequence (NMTS) of the BPV1 E8/E2 protein — the shortest known NMTS

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