title: Spliced MDM2 isoforms promote mutant p53 accumulation and gain-of-function in tumorigenesis.
abstract: The tumour suppressor p53 is frequently mutated in tumours. Mutant p53 (Mutp53) proteins often gain new activities in promoting tumorigenesis, defined as gain-of-function (GOF). Mutp53 can accumulate to high levels in tumours, which promotes mutp53 GOF in tumorigenesis. The mechanism of mutp53 accumulation is poorly understood. Here we find that MDM2 isoforms promote mutp53 accumulation in tumours. MDM2 isoform B (MDM2-B), the MDM2 isoform most frequently over-expressed in human tumours, interacts with full-length MDM2 to inhibit MDM2-mediated mutp53 degradation, promoting mutp53 accumulation and GOF in tumorigenesis. Furthermore, MDM2-B overexpression correlates with mutp53 accumulation in human tumours. In mutp53 knock-in mice, a MDM2 isoform similar to human MDM2-B is overexpressed in the majority of tumours, which promotes mutp53 accumulation and tumorigenesis. Thus, overexpression of MDM2 isoforms promotes mutp53 accumulation in tumours, contributing to mutp53 GOF in tumorigenesis. This may be an important mechanism by which MDM2 isoforms promote tumorigenesis.
authors.affiliation: Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.|Key laboratory of hepatosplenic surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
authors.forename: Tongsen
authors.initials: T
authors.lastname: Zheng
authors.affiliation: Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.|Key laboratory of hepatosplenic surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
authors.forename: Jiabei
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.|Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Cen
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Meihua
authors.initials: M
authors.lastname: Lin
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Xiaowen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.|Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Yu
authors.affiliation: Key laboratory of hepatosplenic surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, 150086, China.
authors.forename: Lianxin
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Feng
authors.affiliation: Department of Pediatrics, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.|Department of Radiation Oncology, Rutgers Cancer Institute of New Jersey, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.|Department of Pharmacology, Robert Wood Johnson Medical School, Rutgers State University of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Wenwei
authors.initials: W
authors.lastname: Hu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D015179:Colorectal Neoplasms / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009154:Mutation; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D025801:Ubiquitin / Q000737:chemistry
chemical_list: D020033:Protein Isoforms; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2