title: The p53 inhibitor Mdm4 cooperates with multiple genetic lesions in tumourigenesis.
abstract: The p53 inhibitor Mdm4 is present at high levels in multiple human cancers. Overexpression of Mdm4 in mice drives the spontaneous development of mostly lymphomas and sarcomas. In this study, we explored the ability of Mdm4 to cooperate with lesions in tumour development. The Mdm4 transgene contributed to mammary tumour development in a BALB/cJ background. High levels of Mdm4 enhanced tumour development in a mutant p53R172H heterozygous background, and reduced the need to lose the wild-type p53 allele, as compared with mice heterozygous only for the p53R172H mutation. Additionally, high levels of Mdm4 cooperated with an oncogenic K-ras mutation to drive lung tumourigenesis in vivo. Finally, we examined p53-independent functions of Mdm4 by studying the contribution of Mdm4 to tumour development in the absence of p53. Whereas the overall survival times of p53-null mice with and without the Mdm4 transgene were similar, male mice with both alterations showed significantly shorter survival than p53-null male mice, and showed differences in tumour spectrum, demonstrating a p53-independent function of Mdm4 in tumourigenesis. Furthermore, p53-null mice with the highest level of Mdm4 tended to have multiple tumours. Thus, a detailed analysis of Mdm4 transgenic mice in various genetic backgrounds shows synergy in tumour development in vivo. Mdm4 may thus serve as a therapeutic target in cancers. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Shunbin
authors.initials: S
authors.lastname: Xiong
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Vinod
authors.initials: V
authors.lastname: Pant
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Neeraj K
authors.initials: NK
authors.lastname: Aryal
authors.affiliation: Department of Hematopathology, The University of Texas MD. Anderson Cancer Center, Houston, TX, USA.
authors.forename: M James
authors.initials: MJ
authors.lastname: You
authors.affiliation: Department of Carcinogenesis, Science Park Research Division, MD Anderson Cancer Center, University of Texas, Smithville, TX, USA.
authors.forename: Donna
authors.initials: D
authors.lastname: Kusewitt
authors.affiliation: Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Guillermina
authors.initials: G
authors.lastname: Lozano
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D019656:Loss of Heterozygosity; D008223:Lymphoma / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D012509:Sarcoma / Q000235:genetics* / Q000473:pathology; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53
keywords: lung adenocarcinoma; mammary tumour genesis; p53 LOH; p53-independent function