RESUMEN
The ubiquitin-proteasome system is a vital protein degradation system that is involved in various cellular processes, such as cell cycle progression, apoptosis, and differentiation. Dysregulation of this system has been implicated in numerous diseases, including cancer, vascular disease, and neurodegenerative disorders. Induction of cellular senescence in hepatocellular carcinoma (HCC) is a potential anticancer strategy, but the precise role of the ubiquitin-proteasome system in cellular senescence remains unclear. In this study, we show that the E3 ubiquitin ligase, TRIM22, plays a critical role in the cellular senescence of HCC cells. TRIM22 expression is transcriptionally upregulated by p53 in HCC cells experiencing ionizing radiation (IR)-induced senescence. Overexpression of TRIM22 triggers cellular senescence by targeting the AKT phosphatase, PHLPP2. Mechanistically, the SPRY domain of TRIM22 directly associates with the C-terminal domain of PHLPP2, which contains phosphorylation sites that are subject to IKKß-mediated phosphorylation. The TRIM22-mediated PHLPP2 degradation leads to activation of AKT-p53-p21 signaling, ultimately resulting in cellular senescence. In both human HCC databases and patient specimens, the levels of TRIM22 and PHLPP2 show inverse correlations at the mRNA and protein levels. Collectively, our findings reveal that TRIM22 regulates cancer cell senescence by modulating the proteasomal degradation of PHLPP2 in HCC cells, suggesting that TRIM22 could potentially serve as a therapeutic target for treating cancer.
Asunto(s)
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/genética , Complejo de la Endopetidasa Proteasomal , Proteínas Proto-Oncogénicas c-akt , Proteína p53 Supresora de Tumor/genética , Neoplasias Hepáticas/genética , Senescencia Celular/genética , Ubiquitinas , Proteínas de Motivos Tripartitos/genética , Proteínas Represoras , Antígenos de Histocompatibilidad Menor , Fosfoproteínas Fosfatasas/genéticaRESUMEN
Cellular senescence, a hallmark of aging, is defined as irreversible cell cycle arrest in response to various stimuli. It plays both beneficial and detrimental roles in cellular homeostasis and diseases. Quality control (QC) is important for the proper maintenance of cellular homeostasis. The QC machineries regulate the integrity of RNA and protein by repairing or degrading them, and are dysregulated during cellular senescence. QC dysfunction also contributes to multiple age-related diseases, including cancers and neurodegenerative, muscle, and cardiovascular diseases. In this review, we describe the characters of cellular senescence, discuss the major mechanisms of RNA and protein QC in cellular senescence and aging, and comprehensively describe the involvement of these QC machineries in age-related diseases. There are many open questions regarding RNA and protein QC in cellular senescence and aging. We believe that a better understanding of these topics could propel the development of new strategies for addressing age-related diseases.