ABSTRACT
Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2'-deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon gamma (IFNgamma), IFNbeta and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy.
Subject(s)
Bromodeoxyuridine/pharmacology , Cellular Senescence/drug effects , Cytokines/metabolism , Distamycins/pharmacology , Signal Transduction/drug effects , Blotting, Western , Cell Line, Tumor , Cytokines/genetics , Drug Synergism , HeLa Cells , Humans , Interferons/genetics , Interferons/metabolism , Interleukin-10/genetics , Interleukin-10/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Interleukin-8/genetics , Interleukin-8/metabolism , Interleukins/genetics , Interleukins/metabolism , Janus Kinase 1/genetics , Janus Kinase 1/metabolism , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/metabolismABSTRACT
Deletion and mutational analysis of the promoter P-dapA from Corynebacterium glutamicum was performed to identify regions and particular nucleotides important for its function. An extended -10 region and a stretch of six T's at positions -55 to -50 were found to be the most important elements in the promoter function. The results of mutational analysis of P-dapA are consistent with the conclusions of statistical computer-aided analysis of 44 C. glutamicum promoter sequences.
