title: Np9, a cellular protein of retroviral ancestry restricted to human, chimpanzee and gorilla, binds and regulates ubiquitin ligase MDM2.
abstract: Humans and primates are long-lived animals with long reproductive phases. One factor that appears to contribute to longevity and fertility in humans, as well as to cancer-free survival, is the transcription factor and tumor suppressor p53, controlled by its main negative regulator MDM2. However, p53 and MDM2 homologs are found throughout the metazoan kingdom from Trichoplacidae to Hominidae. Therefore the question arises, if p53/MDM2 contributes to the shaping of primate features, then through which mechanisms. Previous findings have indicated that the appearances of novel p53-regulated genes and wild-type p53 variants during primate evolution are important in this context. Here, we report on another mechanism of potential relevance. Human endogenous retrovirus K subgroup HML-2 (HERV-K(HML-2)) type 1 proviral sequences were formed in the genomes of the predecessors of contemporary Hominoidea and can be identified in the genomes of Nomascus leucogenys (gibbon) up to Homo sapiens. We previously reported on an alternative splicing event in HERV-K(HML-2) type 1 proviruses that can give rise to nuclear protein of 9 kDa (Np9). We document here the evolution of Np9-coding capacity in human, chimpanzee and gorilla, and show that the C-terminal half of Np9 binds directly to MDM2, through a domain of MDM2 that is known to be contacted by various cellular proteins in response to stress. Np9 can inhibit the MDM2 ubiquitin ligase activity toward p53 in the cell nucleus, and can support the transactivation of genes by p53. Our findings point to the possibility that endogenous retrovirus protein Np9 contributes to the regulation of the p53-MDM2 pathway specifically in humans, chimpanzees and gorillas.
authors.affiliation: a José Carreras Center and Internal Medicine I; University of Saarland Medical Center ; Homburg , Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Heyne
authors.forename: Kathrin
authors.initials: K
authors.lastname: Kölsch
authors.forename: Marine
authors.initials: M
authors.lastname: Bruand
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kremmer
authors.forename: Friedrich A
authors.initials: FA
authors.lastname: Grässer
authors.forename: Jens
authors.initials: J
authors.lastname: Mayer
authors.forename: Klaus
authors.initials: K
authors.lastname: Roemer
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D019143:Evolution, Molecular; D015686:Gene Products, env / Q000502:physiology*; D006071:Gorilla gorilla / Q000235:genetics; D006801:Humans; D002679:Pan troglodytes / Q000235:genetics; D011485:Protein Binding; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D015686:Gene Products, env; C469430:Np9 protein, HERV-K, human; C495901:TP53 protein, human; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2
keywords: MDM2; Np9; endogenous retrovirus; evolution; p53; ubiquitylation