title: [Cisplatin-induced apoptotic endonuclease EndoG inhibits telomerase activity and causes malignant transformation of human CD4+ T lymphocytes].
abstract: Alternative splicing of telomerase catalytic subunit hTERT pre-mRNA (human Telomerase Reverse Transcriptase) regulates telomerase activity. Increased expression of non-active splice variant hTERT results in inhibition of telomerase. Apoptotic endonuclease EndoG is known to participate in hTERT alternative splicing. Expression of EndoG can be induced in response to DNA damages. The aim of this study was to determine the ability of a DNA-damaging compound, cisplatin, to induce EndoG and its influence on alternative splicing of hTERT and telomerase activity in human CD4+ Т lymphocytes. Overexpression of EndoG in CD4+ T cells downregulated the expression of active full-length hTERT variant and upregulated its non-active spliced variant. Reduction of full-length hTERT caused downregulation of telomerase activity, shortening of telomeres length during cell divisions, converting cells to the replicative senescence state, activation of apoptosis and finally cell death. Few cells survived and underwent malignant transformation. Transformed cells have increased telomerase activity and proliferative potential compare to initial CD4+ T cells. These cells have phenotype of T lymphoblastic leukemic cells and are able to form tumors and cause death in experimental mice.
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia; Peoples Friendship University of Russia, Ecological Faculty, Moscow, Russia.
authors.forename: D D
authors.initials: DD
authors.lastname: Zhdanov
authors.affiliation: Peoples Friendship University of Russia, Ecological Faculty, Moscow, Russia.
authors.forename: D А
authors.initials: DА
authors.lastname: Vasina
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Puschino, Moscow region, Russia.
authors.forename: E V
authors.initials: EV
authors.lastname: Orlova
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: V S
authors.initials: VS
authors.lastname: Orlova
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia; Peoples Friendship University of Russia, Ecological Faculty, Moscow, Russia.
authors.forename: V S
authors.initials: VS
authors.lastname: Pokrovsky
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: M V
authors.initials: MV
authors.lastname: Pokrovskaya
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: S S
authors.initials: SS
authors.lastname: Aleksandrova
authors.affiliation: Institute of Biomedical Chemistry, Moscow, Russia.
authors.forename: N N
authors.initials: NN
authors.lastname: Sokolov
mesh_terms: D017398:Alternative Splicing / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D002945:Cisplatin / Q000633:toxicity*; D004706:Endodeoxyribonucleases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008223:Lymphoma / Q000235:genetics / Q000276:immunology / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D061251:Primary Cell Culture; D016019:Survival Analysis; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000187:drug effects; D059506:Telomere Shortening / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C509186:TERT protein, human; D019098:Telomerase; D004706:Endodeoxyribonucleases; C052391:endonuclease G; D002945:Cisplatin
keywords: EndoG; alternative splicing; cisplatin; hTERT; malignant transformation; telomerase