title: MDM2 regulates a novel form of incomplete neoplastic transformation of Theileria parva infected lymphocytes.
abstract: Our efforts are concerned with identifying features of incomplete malignant transformation caused by non viral pathogens. Theileria parva (T. parva) is a tick-transmitted protozoan parasite that can cause a fatal lymphoproliferative disease in cattle. The T. parva-infected lymphocytes display a transformed phenotype and proliferate in culture media like the other tumor cells, however those cells will return to normal after antiprotozoal treatment reflecting the incomplete nature of transformation. To identify signaling pathways involved in this form of transformation of T. parva-infected cells, we screened a library of anticancer compounds. Among these, TIBC, a specific inhibitor of MDM2, markedly inhibited proliferation of T. parva-infected lymphocytes and promoted apoptosis. Therefore we analyzed MDM2 function in T. parva-infected cells. Several T. parva-infected cell lines showed increased expression level of MDM2 with alternatively spliced isoforms compared to the lymphoma cells or ConA blasts. In addition, buparvaquone affected MDM2 expression in T. parva transformed cells. Moreover, p53 protein accumulation and function were impaired in T. parva-infected cells after cisplatin induced DNA damage despite the increased p53 transcription level. Finally, the treatment of T. parva-infected cells with boronic-chalcone derivatives TIBC restored p53 protein accumulation and induced Bax expression. These results suggest that the overexpression of MDM2 is closely linked to the inhibition of p53-dependent apoptosis of T. parva-infected lymphocytes. Aberrant expression of host lymphocyte MDM2 induced by cytoplasmic existence of T. parva, directly and/or indirectly, is associated with aspects of this type of transformation of T. parva-infected lymphocytes. This form of transformation shares features of oncogene induced malignant phenotype acquisition.
authors.affiliation: Division of Collaboration and Education, Hokkaido University, Research Center for Zoonosis Control, Sapporo 001-0020, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Hayashida
authors.forename: Kiichi
authors.initials: K
authors.lastname: Kajino
authors.forename: Masakazu
authors.initials: M
authors.lastname: Hattori
authors.forename: Maura
authors.initials: M
authors.lastname: Wallace
authors.forename: Ivan
authors.initials: I
authors.lastname: Morrison
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sugimoto
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D002417:Cattle; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000187:drug effects; D004789:Enzyme Activation; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D009285:Naphthoquinones / Q000494:pharmacology; D020033:Protein Isoforms; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000469:parasitology* / Q000473:pathology; D016797:Theileria parva / Q000276:immunology / Q000472:pathogenicity*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D016328:NF-kappa B; D009285:Naphthoquinones; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C046326:buparvaquone; D051736:Proto-Oncogene Proteins c-mdm2; D002945:Cisplatin