Functional analysis of the p57KIP2 gene mutation in Beckwith-Wiedemann syndrome.

Details

Serval ID
serval:BIB_B0147DDDCCB8
Type
Article: article from journal or magazin.
Collection
Publications
Title
Functional analysis of the p57KIP2 gene mutation in Beckwith-Wiedemann syndrome.
Journal
Human genetics
Author(s)
Bhuiyan Z.A., Yatsuki H., Sasaguri T., Joh K., Soejima H., Zhu X., Hatada I., Morisaki H., Morisaki T., Mukai T.
ISSN
0340-6717 (Print)
ISSN-L
0340-6717
Publication state
Published
Issued date
03/1999
Peer-reviewed
Oui
Volume
104
Number
3
Pages
205-210
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
p57KIP2 is a potent tight-binding inhibitor of several G1 cyclin/cyclin-dependent kinase (Cdk) complexes, and is a negative regulator of cell proliferation. The gene encoding p57KIP2 is located at 11p15.5, a region implicated in both sporadic cancers and Beckwith-Wiedemann syndrome (BWS). Previously we demonstrated that p57KIP2 is imprinted and only the maternal allele is expressed in both mice and humans. We also showed mutations found in p57KIP2 in patients with BWS that were transmitted from the patients' carrier mothers, indicating that the expressed maternal allele was mutant and that the repressed paternal allele was normal. In the study reported here, we performed functional analysis of the two mutated p57KIP2 genes. We showed that the nonsense mutation found in the Cdk inhibitory domain in a BWS patient rendered the protein inactive with consequent complete loss of its role as a cell cycle inhibitor and of its nuclear localization. We also showed that the mutation in the QT domain, although completely retaining its cell cycle regulatory activity, lacked nuclear localization and was thus prevented from performing its role as an active cell cycle inhibitor. Consequently, no active p57KIP2 would have existed, which might have caused the disorders in BWS patients.

Keywords
Animals, Beckwith-Wiedemann Syndrome/genetics, CDC2-CDC28 Kinases, COS Cells, Cell Nucleus/enzymology, Cyclin-Dependent Kinase 2, Cyclin-Dependent Kinase Inhibitor p57, Cyclin-Dependent Kinases/antagonists & inhibitors, Escherichia coli/genetics, Fluorescent Antibody Technique, Gene Expression Regulation, Bacterial, Humans, Mutation, Nuclear Proteins/genetics, Nuclear Proteins/isolation & purification, Nuclear Proteins/metabolism, Plasmids/genetics, Protein-Serine-Threonine Kinases/antagonists & inhibitors, Recombinant Fusion Proteins/genetics, Recombinant Fusion Proteins/isolation & purification, Recombinant Fusion Proteins/metabolism
Pubmed
Web of science
Create date
01/03/2018 15:41
Last modification date
27/09/2021 10:17
Usage data