ArticlePLoS genetics2013
A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype.
Article in PLoS genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 150 citations in OpenAlex.
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- Variations in the OsGGP uORF Fine-Tune Vitamin C Content and Confer Resistance to Osmotic Stress in Rice.Rice (New York, N.Y.) · 2025Article
- Ribo-Seq Analysis-Based Elucidation of the Dynamic Translation Landscape of Yak Ovarian Tissues in Different Reproductive Stages.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- A core driver gene set identified based on geMER reveals its potential driver mechanism in pan-cancer.NPJ precision oncology · 2025Article
- MCTS2 and distinct eIF2D roles in uORF-dependent translation regulation revealed by in vitro re-initiation assays.The EMBO journal · 2025Article
- Pituitary Neuroendocrine Tumors in Multiple Endocrine Neoplasia.Endocrinology and metabolism (Seoul, Korea) · 2025Review
- Non-canonical translation in cancer: significance and therapeutic potential of non-canonical ORFs, mCell death discovery · 2024Review
- Menin in Cancer.Genes · 2024Review
- Childhood Multiple Endocrine Neoplasia (MEN) Syndromes: Genetics, Clinical Heterogeneity and Modifying Genes.Journal of clinical medicine · 2024Review
- Familial states of primary hyperparathyroidism: an update.Journal of endocrinological investigation · 2024Review
- Upstream open reading frames: new players in the landscape of cancer gene regulation.NAR cancer · 2024Review
- Tall stature and gigantism in transition age: clinical and genetic aspects-a literature review and recommendations.Journal of endocrinological investigation · 2024Review
- ProTInSeq: transposon insertion tracking by ultra-deep DNA sequencing to identify translated large and small ORFs.Nature communications · 2024Article
- Shining a light on the dark proteome: Non-canonical open reading frames and their encoded miniproteins as a new frontier in cancer biology.Protein science : a publication of the Protein Society · 2023Review
- An update on, and genetics of refractory adenomas of childhood.Pituitary · 2023Review
- CrypticProteinDB: an integrated database of proteome and immunopeptidome derived non-canonical cancer proteins.NAR cancer · 2023Article
- Novel germline variants of CDKN1B and CDKN2C identified during screening for familial primary hyperparathyroidism.Journal of endocrinological investigation · 2023Article
- Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5'UTRs.Nucleic acids research · 2023Article
- The Functional Meaning of 5'UTR in Protein-Coding Genes.International journal of molecular sciences · 2023Review
- Multiple endocrine neoplasia type 4: a new member of the MEN family.Endocrine connections · 2023Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 7 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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