Destabilisation, aggregation, toxicity and cytosolic mislocalisation of nucleophosmin regions associated with acute myeloid leukemia(276 visite) Scognamiglio PL, Di Natale C, Leone M, Cascella R, Cecchi C, Lirussi L, Antoniali G, Riccardi D, Morelli G, Tell G, Chiti F, Marasco D
Oncotarget (ISSN: 1949-2553, 1949-2553electronic), 2016 Aug 1; N/D: N/D-N/D.
Tipo di articolo: Journal Article,
Impact factor: 5.168, Impact factor a 5 anni: 5.312
Url: Non disponibile.
Parole chiave: Aml, Cd Spectroscopy, Aggregation Phenomena, Helical Peptides,
*** IBB - CNR *** Department of Pharmacy, CIRPEB: Centro Interuniversitario di Ricerca sui Peptidi Bioattivi-University of Naples "Federico II", DFM-Scarl, 80134, Naples, Italy., Permanent address: Center for Advanced Biomaterials for Health Care@CRIB Istituto Italiano di Tecnologia, 80125 Napoli, Italy., Institute of Biostructures and Bioimaging - CNR, 80134, Naples, Italy., Section of Biochemistry, Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, 50134, Florence, Italy., Laboratory of Molecular Biology and DNA repair, Department of Medical and Biological Sciences, University of Udine, 33100, Udine, Italy., Permanent address: Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, Nordbyhagen, 1474, Norway.,
Nucleophosmin (NPM1) is a multifunctional protein that is implicated in the pathogenesis of several human malignancies. To gain insight into the role of isolated fragments of NPM1 in its biological activities, we dissected the C-terminal domain (CTD) into its helical fragments. Here we focus the attention on the third helix of the NPM1-CTD in its wild-type (H3 wt) and AML-mutated (H3 mutA and H3 mutE) sequences. Conformational studies, by means of CD and NMR spectroscopies, showed that the H3 wt peptide was partially endowed with an alpha-helical structure, but the AML-sequences exhibited a lower content of this conformation, particularly the H3 mutA peptide. Thioflavin T assays showed that the H3 mutE and the H3 mutA peptides displayed a significant aggregation propensity that was confirmed by CD and DLS assays. In addition, we found that the H3 mutE and H3 mutA peptides, unlike the H3 wt, were moderately and highly toxic, respectively, when exposed to human neuroblastoma cells. Cellular localization experiments confirmed that the mutated sequences hamper their nucleolar accumulation, and more importantly, that the helical conformation of the H3 region is crucial for such a localization.
12 Records (11 escludendo Abstract e Conferenze). Impact factor totale: 49.016 (44.828 escludendo Abstract e Conferenze). Impact factor a 5 anni totale: 48.998 (41.835 escludendo Abstract e Conferenze).