Feedback between p21 and reactive oxygen production is necessary for cell senescence

By J. Passos, Glyn Nelson, Chunfang Wang, C. Simillion, C. Proctor, Satomi Miwa, Sharon Olijslagers, J. Hallinan, A. Wipat, G. Saretzki and 3 more. Molecular Systems Biology, 2010

963 citations recorded by the source corpus.

Cellular senescence—the permanent arrest of cycling in normally proliferating cells such as fibroblasts—contributes both to age‐related loss of mammalian tissue homeostasis and acts as a tumour suppressor mechanism. The pathways leading to establishment of senescence are proving to be more complex than was previously envisaged. Combining in‐silico interactome analysis and functional target gene inhibition, stochastic modelling and live cell microscopy, we show here that there exists a dynamic feedback loop that is triggered by a DNA damage response (DDR) and, which after a delay of several days, locks the cell into an actively maintained state of ‘deep’ cellular senescence. The essential feature of the loop is that long‐term activation of the checkpoint gene CDKN1A (p21) induces mitochondrial dysfunction and production of reactive oxygen species (ROS) through serial signalling through GADD45‐MAPK14(p38MAPK)‐GRB2‐TGFBR2‐TGFβ. These ROS in turn replenish short‐lived DNA damage foci and maintain an ongoing DDR. We show that this loop is both necessary and sufficient for the stability of growth arrest during the establishment of the senescent phenotype.

Subfields: Molecular Biology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/4db02f60a57dd7accf4cc5b9774f1eb214e78141

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In Molecular Biology

1. J. Campisi
2. M. Demaria
3. J. Kirkland
4. Adam Freund
5. Manuel Serrano
6. T. Tchkonia
7. D. Peeper
8. T. Kuilman

In Oncology

1. J. Campisi
2. J. Kirkland
3. P. Jat
4. R. Kumari
5. Adam Freund
6. M. Collado
7. Manuel Serrano
8. E. Verdin

In Physiology

1. J. Campisi
2. J. Kirkland
3. M. Demaria
4. T. Tchkonia
5. Manuel Serrano
6. Adam Freund
7. Jesús Gil
8. D. Peeper

Citations in the corpus

• Mitochondrial dysfunction in cell senescence and aging (2022, background): “During mitochondrial dysfunction, low MMP is typically associated with increased production of reactive oxygen species (ROS) (32, 33); however, empirical determination of ROS is required for each case to confirm this.”
• Cellular Senescence: A Translational Perspective (2017, background): “An essential part of SAMDappears to be a decrease in mitochondrial membrane potential related to mitochondrial membrane permeabilization (Passos et al., 2010, Passos et al., 2007).”
• Aging, Cellular Senescence, and Cancer (2012, background): “Such signaling is also accompanied by the slow (occurring over days) activation of other signaling pathways, such as those governed by the stress-responsive p38MAPK and protein kinase C pathways, and increased reactive oxygen species, which also participate in signaling pathways (53, 57, 76, 77) (Fi”
• p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phenotype (2011, background): “In the presence of existing DNA damage, p38MAPK can replenish short-lived DNA damage foci via an ROS feedback loop (Passos et al, 2010).”
• The essence of senescence. (2010, background): “A recent systems biology study has suggested that ROS mediates senescence through induction of DNA damage foci, with a contribution of p21CIP1 (Passos et al. 2010).”
• Cellular Senescence: Defining a Path Forward. (2019, background): “Mitochondria in senescentcellsarelessfunctional,showingdecreasedmembrane potential, increased proton leak, reduced fusion and fission rates, increased mass, and abundance of tricarboxylic acid (TCA) cycle metabolites (Kaplon et al., 2013; Passos et al., 2010).”
• A senescent cell bystander effect: senescence-induced senescence (2012, background): “However, various ROS species are readily interchangeable, and hydrogen peroxide is easily membrane permeable, so that extracellular antioxidants will effectively reduce intracellular ROS concentrations.”
• Cellular senescence and its effector programs (2014, background): “As discussed later, such a ‘‘spectrum’’ of senescence is consistent with the recent idea of an actively maintained state of ‘‘deep’’ or ‘‘late’’ senescence, which seems to be associated with specific (or additional) markers and effectors of senescence (Passos et al. 2010; De Cecco et al. 2013; Ivano”
• Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021, background): “…proteostasis, mitochondrial dysfunction, inflammation, and/or tissue damage signals, irradiation, or chemotherapeutic agents, nutrient deprivation (Di Micco et al., 2006; Kuilman et al., 2010; Passos et al., 2010; Pazolli et al., 2012; García-Prat et al., 2016; Mikuła-Pietrasik et al., 2020).”
• The Mitochondrial Basis of Aging (2016, background): “including the p53 target and cell-cycle regulator p21, which also appears to regulate senescence in a redox-dependent fashion (Macip et al., 2002; Passos et al., 2010).”