title: TRIM28/KAP1 regulates senescence.
abstract: Senescence is a highly stable cell cycle arrest which limits the replication of cells with damaged genomes. The senescence program is activated during aging or in response to insults like DNA damage or oncogenic signaling. Upon induction of senescence, cells undergo profound changes on their transcription program, chromatin organization, and they secrete a complex mixture of mainly pro-inflammatory components termed the senescence-associated secretory phenotype (SASP). The SASP mediates multiple effects, including reinforcing senescence and activating immune surveillance responses. Given the important role that senescence has in aging, cancer and other pathologies, identifying mechanisms regulating senescence has therapeutic potential. Here we describe a role for TRIM28 (also known as KRAB-associated protein 1, KAP1) on mediating oncogene-induced senescence (OIS). TRIM28 accumulates during OIS becoming phosphorylated on serine 824. To investigate the role of TRIM28, we knocked down its expression and observed that the depletion of TRIM28 partially prevented cell arrest during OIS. While induction of p53 and p21 during OIS, was not affected by TRIM28 depletion, p16(INK4a) induction was partially prevented. Finally, we observed that the induction of IL8, IL6 and other SASP components were strongly suppressed upon TRIM28 depletion. In conclusion, the above-described results show that TRIM28 regulates senescence and affects the induction of the senescence-associated secretory phenotype.
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Santos
authors.affiliation: Cell Proliferation Group, MRC Clinical Sciences Centre, Imperial College London, Hammersmith Campus, London W12 0NN, UK. Electronic address: jesus.gil@csc.mrc.ac.uk.
authors.forename: Jesús
authors.initials: J
authors.lastname: Gil
mesh_terms: D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D009857:Oncogenes; D010766:Phosphorylation; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D018836:Inflammation Mediators; D012097:Repressor Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28
keywords: SASP; Senescence; TRIM28; p16