Abstract
The cellular changes occurring due to senescence like proliferation arrest, increase in free radical levels, and secretion of pro-inflammatory cytokines have been well studied, but its associated alteration in intracellular signalling networks has been scarcely explored. In this study, we examine the roles of three major kinases viz. p38 MAPK, ERK, and STAT3 in regulating iNOS expression and thereby the levels of the free radical Nitric oxide in senescent cells. Our study revealed that these kinases could differentially regulate iNOS in senescent cells compared to non-senescent cells. Further, we tested the physiological relevance of these alterations with Salmonella infection assays and established an inter-regulatory network between these kinases unique to infected senescent cells. Overall, our findings show how key signalling networks may be rewired in senescent cells rendering them phenotypically different.
Highlights
Senescence is defined as a state of irreversible cell cycle arrest wherein intrinsic permanent changes prevent the cell from undergoing division even in the presence of appropriate mitogenic cues (Hernandez-segura et al, 2018)
Cells are treated with BrdU, a genotoxic agent which induces only DNA damage and subsequently activates the DNA damage response (DDR) signalling cascade resulting in proliferation arrest and senescence (Eriko et al, 1999; Minagawa et al, 2005; Rossa et al, 2008; Le et al, 2010; Nair et al, 2014; Nair et al, 2018; Ozsvari et al, 2018)
Patients suffering from Chronic Obstructive Pulmonary Disorders (COPD) and cigarette smokers show a higher prevalence of senescent cells in the lungs (Nyunoya et al, 2006; Vij et al, 2018; Parikh et al, 2019)
Summary
Senescence is defined as a state of irreversible cell cycle arrest wherein intrinsic permanent changes prevent the cell from undergoing division even in the presence of appropriate mitogenic cues (Hernandez-segura et al, 2018). The quest to identify factors contributing to this divisional arrest led to the discovery of persistent DNA damage as one of the major triggers caused by telomere attrition, oxidative or genotoxic stress (López-Otıń et al, 2013; Rossiello et al, 2014; Salama et al, 2014; Hernandez-segura et al, 2018) Following this discovery, several groups have elucidated the role of DNA damage response (DDR) signalling in senescence induction and many proteins involved in the signalling cascade like gH2A.x and p53 binding protein (53BP1) have emerged as important markers of cellular senescence, in addition to cell cycle checkpoint proteins like p21 and p16 (Chen et al, 2007; Baker and Fruk, 2021). These include their ability to secrete several factors comprising the Senescence Associated Secretory Phenotype (SASP) that can alter its surrounding micro-environment (Coppé et al, 2008; Coppé et al, 2010), their comparatively higher resistance to apoptosis when insulted by certain stressors (Soto-gamez et al, 2019; Ogrodnik, 2021) and accumulation of free radicals like Reactive Oxygen Species (ROS) and Nitric Oxide (NO) (Davalli et al, 2016; Liguori et al, 2018).
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