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A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2)

p57(Kip2) 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 o...

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Autores principales: Stampone, Emanuela, Bencivenga, Debora, Barone, Clementina, Di Finizio, Marilena, Della Ragione, Fulvio, Borriello, Adriana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305445/
https://www.ncbi.nlm.nih.gov/pubmed/34299047
http://dx.doi.org/10.3390/ijms22147428
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author Stampone, Emanuela
Bencivenga, Debora
Barone, Clementina
Di Finizio, Marilena
Della Ragione, Fulvio
Borriello, Adriana
author_facet Stampone, Emanuela
Bencivenga, Debora
Barone, Clementina
Di Finizio, Marilena
Della Ragione, Fulvio
Borriello, Adriana
author_sort Stampone, Emanuela
collection PubMed
description p57(Kip2) 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 p57(Kip2), 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-p57(Kip2)). We found a clear redistribution of R316W-p57(Kip2), in that while the wild-type p57(Kip2) mostly occurs in the nucleus, the mutant form is also distributed in the cytoplasm. Transfection of two expression constructs encoding the p57(Kip2) 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), p57(Kip2) was confined in the cytosol, implying that this sequence is absolutely required for nuclear entry. In conclusion, we identified an unreported p57(Kip2) NLS and suggest that its absence or mutation might be of relevance in CDKN1C-associated human diseases determining significant changes of p57(Kip2) localization/regulatory roles.
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spelling pubmed-83054452021-07-25 A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2) Stampone, Emanuela Bencivenga, Debora Barone, Clementina Di Finizio, Marilena Della Ragione, Fulvio Borriello, Adriana Int J Mol Sci Article p57(Kip2) 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 p57(Kip2), 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-p57(Kip2)). We found a clear redistribution of R316W-p57(Kip2), in that while the wild-type p57(Kip2) mostly occurs in the nucleus, the mutant form is also distributed in the cytoplasm. Transfection of two expression constructs encoding the p57(Kip2) 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), p57(Kip2) was confined in the cytosol, implying that this sequence is absolutely required for nuclear entry. In conclusion, we identified an unreported p57(Kip2) NLS and suggest that its absence or mutation might be of relevance in CDKN1C-associated human diseases determining significant changes of p57(Kip2) localization/regulatory roles. MDPI 2021-07-11 /pmc/articles/PMC8305445/ /pubmed/34299047 http://dx.doi.org/10.3390/ijms22147428 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Stampone, Emanuela
Bencivenga, Debora
Barone, Clementina
Di Finizio, Marilena
Della Ragione, Fulvio
Borriello, Adriana
A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2)
title A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2)
title_full A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2)
title_fullStr A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2)
title_full_unstemmed A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2)
title_short A Beckwith–Wiedemann-Associated CDKN1C Mutation Allows the Identification of a Novel Nuclear Localization Signal in Human p57(Kip2)
title_sort beckwith–wiedemann-associated cdkn1c mutation allows the identification of a novel nuclear localization signal in human p57(kip2)
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305445/
https://www.ncbi.nlm.nih.gov/pubmed/34299047
http://dx.doi.org/10.3390/ijms22147428
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