title: Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization.
abstract: The HDMX protein is closely related to HDM2 with which it shares different structural domains, particularly the p53 binding domain and the ring finger domain, where the two HDM proteins interact. Several oncogenic forms derived from splicing of HDM2 have been described in cancer. This work aimed at investigating whether analogous forms of HDMX exist in human tumors. Here, we report the characterization of an aberrantly spliced form of HDMX, HDMX211, isolated from the thyroid tumor cell line, ARO. HDMX211 binds and stabilizes the HDM2 protein. Although it lacks the p53 binding domain, HDMX211 also stabilizes p53 by counteracting its degradation by HDM2. However, the resulting p53 is transcriptionally inactive and increasingly associated to its inhibitor HDM2. Expression of HDMX211 strongly enhances the colony-forming ability of human cells in the presence or absence of wild-type p53. Conversely, depletion of HDMX211 by small interfering RNA significantly reduces the growth of ARO cells and increases their sensitivity to chemotherapy. Screening of lung cancer biopsies shows the presence of HDMX211 in samples that overexpress HDM2 protein, supporting a pathologic role for this new protein. This is the first evidence of a variant form of HDMX that has oncogenic potential independently of p53. HDMX211 reveals a new mechanism for overexpression of the oncoprotein HDM2. Most interestingly, it outlines a possible molecular explanation for a yet unclarified tumor phenotype, characterized by simultaneous overexpression of HDM2 and wild-type p53.
authors.affiliation: Laboratory of Molecular Oncogenesis, Regina Elena Cancer Institute.
authors.forename: Simona
authors.initials: S
authors.lastname: Giglio
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.forename: Francesca
authors.initials: F
authors.lastname: Gentiletti
authors.forename: Giorgia
authors.initials: G
authors.lastname: Sparaco
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.forename: Fabio
authors.initials: F
authors.lastname: Barassi
authors.forename: Carla
authors.initials: C
authors.lastname: Martella
authors.forename: Andrea
authors.initials: A
authors.lastname: Prodosmo
authors.forename: Stefano
authors.initials: S
authors.lastname: Iacovelli
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
authors.forename: Antonella
authors.initials: A
authors.lastname: Farsetti
authors.forename: Silvia
authors.initials: S
authors.lastname: Soddu
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
authors.forename: Ada
authors.initials: A
authors.lastname: Sacchi
authors.forename: Alfredo
authors.initials: A
authors.lastname: Pontecorvi
authors.forename: Fabiola
authors.initials: F
authors.lastname: Moretti
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D018797:Cell Cycle Proteins; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2