Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
20699642
DOI
10.4161/cc.9.15.12521
PII: 12521
Knihovny.cz E-zdroje
- MeSH
- antitumorózní látky farmakologie MeSH
- buněčné jádro účinky léků metabolismus MeSH
- genetická transkripce účinky léků MeSH
- jaderné proteiny genetika metabolismus MeSH
- Janus kinasa 1 metabolismus MeSH
- kompartmentace buňky účinky léků MeSH
- lidé MeSH
- messenger RNA genetika metabolismus MeSH
- nádorové buněčné linie MeSH
- nádorové supresorové proteiny genetika metabolismus MeSH
- nádorový supresorový protein p53 metabolismus MeSH
- nádory enzymologie genetika patologie MeSH
- poškození DNA účinky léků MeSH
- protein promyelocytické leukemie MeSH
- regulace genové exprese u leukemie účinky léků MeSH
- responzivní elementy genetika MeSH
- signální transdukce účinky léků MeSH
- stárnutí buněk účinky léků MeSH
- transkripční faktory STAT metabolismus MeSH
- transkripční faktory genetika metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antitumorózní látky MeSH
- jaderné proteiny MeSH
- Janus kinasa 1 MeSH
- messenger RNA MeSH
- nádorové supresorové proteiny MeSH
- nádorový supresorový protein p53 MeSH
- PML protein, human MeSH Prohlížeč
- protein promyelocytické leukemie MeSH
- transkripční faktory STAT MeSH
- transkripční faktory MeSH
The Promyelocytic leukemia protein (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 5-bromo-2'deoxyuridine (BrdU), thymidine (TMD), distamycin A (DMA), aphidicolin (APH), etoposide (ET) and camptothecin (CPT) all evoke expansion of PML nuclear compartment and its association with persistent DNA lesions in several human cancer cell lines and normal diploid fibroblasts. This phenomenon was accompanied by elevation of PML transcripts after treatment with BrdU, TMD, DMA and CPT. 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. As PML protein stability remained unchanged after drug treatment, decreased protein turnover was unlikely to explain the senescence-associated increased abundance of PML. Furthermore, binding activity of Interferon Stimulated Response Element (ISRE) within the PML gene promoter, and suppression of reporter gene activity after deletion of ISRE from the PML promoter region suggested that drug-induced PML transcription is controlled via transcription factors interacting with this element. Collectively, 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.
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