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Senescence Signaling

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Pathway Description:

Cellular senescence is an adaptive response induced by multiple physiological and pathological stressors, resulting in a permanent state of cell cycle arrest. Senescence provides a defense mechanism to maintain tissue homeostasis and limit tumor formation by enabling tissue remodeling through the sequestration and removal of damaged cells. However, the accumulation of persistent senescent cells has been implicated as a major cause of age-related pathologies and inflammatory diseases. Over five decades ago, Leonard Hayflick and Paul Moorhead reported a seminal discovery that human cells exhibit replicative senescence—a finite proliferative capacity in vitro caused by the progressive shortening of the telomeric regions at the ends of chromosomes—which triggers a DNA damage response (DDR) and leads to cell cycle arrest. Similarly, cellular senescence can result in response to DNA damage by irradiation or chemotherapeutics, as well as tumor suppressor loss, elevated reactive oxygen species, and mitochondrial dysfunction. These stimuli signal via a number of intracellular pathways—including the DDR components ATR, ATM, and p53—which converge on the activation of cyclin dependent kinase inhibitors (CDKIs)—p16, p21, and p27—and lead to hyperphosphorlyation of the retinoblastoma protein (RB) and ultimately, withdrawal from the cell cycle.

Although senescent cells no longer proliferate, they remain metabolically active and display characteristic morphological and physiological changes associated with the state. Namely, senescent cells have an enlarged, flattened shape in vitro and exhibit disrupted nuclear envelope integrity due to decreased expression of lamin B1. The accumulation of β-galactosidase, a result of altered lysosomal activity, is a hallmark of cellular senescence. Chromatin reorganization, specifically the formation of senescence associated heterochromatin foci (SAHF), is a frequently observed biomarker of cells undergoing oncogene-induced senescence and can be detected by immunoreactivity for macroH2A, lysine 9 di-or-tri-methylated histone H3 (H3K9Me2/3), and heterochromatin protein 1 (HP1). Indicators of DNA damage, including the phosphorylation of the Ser-139 residue of the histone variant H2AX (forming γH2AX), can also be examined in combination with additional biomarkers to assess senescence.

Senescent cells often show dramatic changes in their secretome, a phenomenon known as the senescence-associated secretory phenotype (SASP). SASP entails the upregulation and release of many pro-inflammatory cytokines (e.g. IL-6/IL-1β), proteases (MMP3), and growth factors which exert a range of autocrine/paracrine effects on the surrounding tissue microenvironment. SASP has been reported to have both beneficial effects and detrimental consequences depending on cellular context. For example, SASP can recruit immune cells to initiate tissue repair through the removal of damaged cells, but has also been linked to angiogenesis and ECM remodeling to promote tumor cell progression.

Unraveling the mechanisms that underlie cellular senescence and its role in human disease has broad therapeutic implications for age-related pathologies, the promotion of tissue remodeling and regeneration, and the treatment of cancer.

Selected Reviews:

created September 2019

Acetylase
Metabolic Enzyme
Adaptor
Methyltransferase or G-protein
Apoptosis/Autophagy Regulator
Phosphatase
Cell Cycle Regulator
Protein Complex
Deacetylase or Cytoskeletal Protein
Receptor
Growth Factor/Cytokine/Development Protein
Transcription Factor or Translation Factor
GTPase/GAP/GEF
Ubiquitin/SUMO Ligase or Deubiquitinase
Kinase
Other
 
Direct Stimulatory Modification
Direct Stimulatory Modification
Transcriptional Stimulatory Modification
Transcriptional Stimulation
Direct Inhibitory Modification
Direct Inhibitory Modification
Transcriptional Inhibition
Transcriptional Inhibition
Multistep Stimulatory Modification
Multistep Stimulatory Modification
Joining of Subunits
Joining of Subunits
Multistep Inhibitory Modification
Multistep Inhibitory Modification
Translocation
Translocation
Tentative Stimulatory Modification
Tentative Stimulatory Modification
Separation of Subunits or Cleavage Products
Separation of Subunits or Cleavage Products
Tentative Inhibitory Modification
Tentative Inhibitory Modification