Alterations of the Mdm2 C-Terminus Differentially Impact Its Function In Vivo.

Autor:	Pant V; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Aryal NK; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Xiong S; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Chau GP; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas., Fowlkes NW; Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas., Lozano G; Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2022 Apr 01; Vol. 82 (7), pp. 1313-1320.
DOI:	10.1158/0008-5472.CAN-21-2381
Abstrakt:	Murine double minute 2 (Mdm2) is the principal E3-ubiquitin ligase for p53 and contains a C2H2C4 type RING domain wherein the last cysteine residue is followed by an evolutionarily conserved 13 amino acid C-terminal tail. Previous studies have indicated that integrity of the C-terminal tail is critical for Mdm2 function. Recently, a mutation extending the MDM2 length by five amino acids was identified and associated with enhanced p53 response in fibroblasts and premature aging in a human patient. To investigate the importance of the conserved Mdm2 C-terminal length on p53 regulatory function in vivo, we engineered three novel mouse alleles using CRISPR-Cas9 technology. Genetic studies with these murine models showed that curtailing Mdm2 C-terminal length by even a single amino acid leads to p53-dependent embryonic lethality. Extension of the Mdm2 C-terminal length by five amino acids (QLTCL) yielded viable mice that are smaller in size, exhibit fertility problems, and have a shortened life span. Analysis of early passage mouse embryonic fibroblasts indicated impaired Mdm2 function correlates with enhanced p53 activity under stress conditions. Furthermore, analysis in mice showed tissue-specific alterations in p53 target gene expression and enhanced radiosensitivity. These results confirm the physiological importance of the evolutionarily conserved Mdm2 C-terminus in regulating p53 functions. Significance: This in vivo study highlights that alterations to the C-terminus of Mdm2 perturb its regulation of the tumor suppressor p53. (©2022 American Association for Cancer Research.)
Databáze:	MEDLINE
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