A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype

Gianluca Occhi, Daniela Regazzo, Giampaolo Trivellin, Francesca Boaretto, Denis Ciato, Sara Bobisse, Sergio Ferasin, Filomena Cetani, Elena Pardi, Márta Korbonits, Natalia S. Pellegata, Viktoryia Sidarovich, Alessandro Quattrone, Giuseppe Opocher, Franco Mantero, Carla Scaroni

Research output: Contribution to journalArticle

Abstract

The CDKN1B gene encodes the cyclin-dependent kinase inhibitor p27KIP1, an atypical tumor suppressor playing a key role in cell cycle regulation, cell proliferation, and differentiation. Impaired p27KIP1 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 p27KIP1 expression. Our findings demonstrate that, in addition to the previously described mechanisms leading to reduced p27KIP1 activity, such as degradation via the ubiquitin/proteasome pathway or non-covalent sequestration, p27KIP1 activity can also be modulated by an uORF and mutations affecting uORF could change p27KIP1 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.

Original languageEnglish
Article numbere1003350
JournalPLoS Genetics
Volume9
Issue number3
DOIs
Publication statusPublished - 2013

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

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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. (2013). A Novel Mutation in the Upstream Open Reading Frame of the CDKN1B Gene Causes a MEN4 Phenotype. PLoS Genetics, 9(3), [e1003350]. https://doi.org/10.1371/journal.pgen.1003350