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Occhi, G.* ; Regazzo, D.* ; Trivellin, G.* ; Boaretto, F.* ; Ciato, D.* ; Bobisse, S.* ; Ferasin, S.* ; Cetani, F.* ; Pardi, E.* ; Korbonits, M.* ; Pellegata, N.S. ; Sidarovich, V.* ; Quattrone, A.* ; Opocher, G.* ; Mantero, F.* ; Scaroni, C.*

A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype.

PLoS Genet. 9:e1003350 (2013)
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The CDKN1B gene encodes the cyclin-dependent kinase inhibitor p27(KIP1), an atypical tumor suppressor playing a key role in cell cycle regulation, cell proliferation, and differentiation. Impaired p27(KIP1) expression and/or localization are often observed in tumor cells, further confirming its central role in regulating the cell cycle. Recently, germline mutations in CDKN1B have been associated with the inherited multiple endocrine neoplasia syndrome type 4, an autosomal dominant syndrome characterized by varying combinations of tumors affecting at least two endocrine organs. In this study we identified a 4-bp deletion in a highly conserved regulatory upstream ORF (uORF) in the 5'UTR of the CDKN1B gene in a patient with a pituitary adenoma and a well-differentiated pancreatic neoplasm. This deletion causes the shift of the uORF termination codon with the consequent lengthening of the uORF-encoded peptide and the drastic shortening of the intercistronic space. Our data on the immunohistochemical analysis of the patient's pancreatic lesion, functional studies based on dual-luciferase assays, site-directed mutagenesis, and on polysome profiling show a negative influence of this deletion on the translation reinitiation at the CDKN1B starting site, with a consequent reduction in p27(KIP1) expression. Our findings demonstrate that, in addition to the previously described mechanisms leading to reduced p27(KIP1) activity, such as degradation via the ubiquitin/proteasome pathway or non-covalent sequestration, p27(KIP1) activity can also be modulated by an uORF and mutations affecting uORF could change p27(KIP1) expression. This study adds the CDKN1B gene to the short list of genes for which mutations that either create, delete, or severely modify their regulatory uORFs have been associated with human diseases.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Multiple Endocrine Neoplasia ; Inhibitor P27 ; Functional-characterization ; Messenger-rnas ; Cell-cycle ; Translation ; Type-1 ; P27(kip1) ; Reinitiation ; Expression
Language english
Publication Year 2013
HGF-reported in Year 2013
ISSN (print) / ISBN 1553-7390
e-ISSN 1553-7404
Journal PLoS Genetics
Quellenangaben Volume: 9, Issue: 3, Pages: , Article Number: e1003350 Supplement: ,
Publisher Public Library of Science (PLoS)
Reviewing status Peer reviewed
Institute(s) Institute of Pathology (PATH)
POF-Topic(s) 30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Research field(s) Enabling and Novel Technologies
PSP Element(s) G-500300-001
PubMed ID 23555276
DOI 10.1371/journal.pgen.1003350
WOS ID WOS:000316866700027
Scopus ID 84876002553
Erfassungsdatum 2013-04-09
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