A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57Kip2
| Autor: | Adriana Borriello, Emanuela Stampone, Debora Bencivenga, Clementina Barone, Fulvio Della Ragione, Marilena Di Finizio |
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| Přispěvatelé: | Stampone, E., Bencivenga, D., Barone, C., Di Finizio, M., Ragione, F. D., Borriello, A. |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Beckwith-Wiedemann Syndrome CDKN1C mutation Nuclear Localization Signals Mutant Beckwith–Wiedemann syndrome medicine.disease_cause 0302 clinical medicine HEK293 Cell Biology (General) Cell Nucleu Spectroscopy Cellular localization Mutation biology Chemistry Cell Cycle General Medicine Computer Science Applications Cell biology 030220 oncology & carcinogenesis Kip2 R316W-p57 Human CDKN1C mutations congenital hereditary and neonatal diseases and abnormalities QH301-705.5 NLS Hep G2 Cell Catalysis Inorganic Chemistry 03 medical and health sciences Cyclin-dependent kinase R316W-p57Kip2 medicine Physical and Theoretical Chemistry Cyclin-Dependent Kinase Inhibitor p57 p57Kip2 QD1-999 Molecular Biology Cell Proliferation Organic Chemistry medicine.disease P57 030104 developmental biology Cytoplasm biology.protein Nuclear localization sequence |
| Zdroj: | International Journal of Molecular Sciences, Vol 22, Iss 7428, p 7428 (2021) International Journal of Molecular Sciences Volume 22 Issue 14 |
| ISSN: | 1422-0067 |
| DOI: | 10.3390/ijms22147428 |
| Popis: | p57Kip2 protein is a member of the CIP/Kip family, mainly localized in the nucleus where it exerts its Cyclin/CDKs inhibitory function. In addition, the protein plays key roles in embryogenesis, differentiation, and carcinogenesis depending on its cellular localization and interactors. Mutations of CDKN1C, the gene encoding human p57Kip2, result in the development of different genetic diseases, including Beckwith–Wiedemann, IMAGe and Silver–Russell syndromes. We investigated a specific Beckwith–Wiedemann associated CDKN1C change (c.946 C> T) that results in the substitution of the C-terminal amino acid (arginine 316) with a tryptophan (R316W-p57Kip2). We found a clear redistribution of R316W-p57Kip2, in that while the wild-type p57Kip2 mostly occurs in the nucleus, the mutant form is also distributed in the cytoplasm. Transfection of two expression constructs encoding the p57Kip2 N- and C-terminal domain, respectively, allows the mapping of the nuclear localization signal(s) (NLSs) between residues 220–316. Moreover, by removing the basic RKRLR sequence at the protein C-terminus (from 312 to 316 residue), p57Kip2 was confined in the cytosol, implying that this sequence is absolutely required for nuclear entry. In conclusion, we identified an unreported p57Kip2 NLS and suggest that its absence or mutation might be of relevance in CDKN1C-associated human diseases determining significant changes of p57Kip2 localization/regulatory roles. |
| Databáze: | OpenAIRE |
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