Regulation of the PML tumor suppressor in drug-induced senescence of human normal and cancer cells by JAK/STAT-mediated signaling.
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.
Hubackova
Sona
S
Department of Genome Integrity, Institute of Molecular Genetics, v.v.i., Academy of Sciences of the Czech Republic, Prague, Czech Republic.
Novakova
Zora
Z
Krejcikova
Katerina
K
Kosar
Martin
M
Dobrovolna
Jana
J
Duskova
Pavlina
P
Hanzlikova
Hana
H
Vancurova
Marketa
M
Barath
Peter
P
Bartek
Jiri
J
Hodny
Zdenek
Z
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002451:Cell Compartmentation / Q000187:drug effects; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D016922:Cellular Senescence / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D053613:Janus Kinase 1 / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D012333:RNA, Messenger; D050791:STAT Transcription Factors; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D053613:Janus Kinase 1