Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling

0347137 - ÚMG 2011 RIV US eng J - Journal Article
Hubáčková, Soňa - Nováková, Zora - Krejčíková, Kateřina - Košař, Martin - Dobrovolná, Jana - Dušková, Pavlína - Hanzlíková, Hana - Vančurová, Markéta - Barath, P. - Bartek, J. - Hodný, Zdeněk
Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling.
Cell Cycle. Roč. 9, č. 15 (2010), s. 3085-3099. ISSN 1538-4101. E-ISSN 1551-4005
R&D Projects: GA AV ČR IAA500390501; GA ČR GA204/08/1418; GA ČR GA301/08/0353
Institutional research plan: CEZ:AV0Z50520514
Keywords : PML tumor suppressor * cellular senescence * JAK-STAT signaling pathway
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 4.999, year: 2010

PML tumor suppressor is upregulated in several forms of cellular senescence, however the mechanism of its induction is elusive. Here we show that genotoxic drugs that induce senescence, such as bromodeoxyuridine, thymidine, distamycin A, aphidicolin, etoposide and camptothecin evoke expansion of PML nuclear compartment and its association with persistent DNA lesions in several human normal and cancer cells. This phenomenon was accompanied by elevation of PML transcripts. Chemical inhibition of all JAK kinases and RNAi-mediated knock-down of JAK1 suppressed PML expression, implicating JAK/STAT-mediated signaling in regulation of the PML gene. Our data show that upregulation of the PML tumor suppressor in cellular senescence triggered by diverse drugs including clinically used anti-cancer chemotherapeutics relies on stimulation of PML transcription by JAK/STAT-mediated signaling, possibly evoked by the autocrine/paracrine activities of senescence-associated cytokines.
Permanent Link: http://hdl.handle.net/11104/0187982