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老化のシグナル伝達

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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.

参考文献:

作成日:2019年9月

  • キナーゼキナーゼ
  • ホスファターゼホスファターゼ
  • 転写因子転写因子
  • カスパーゼカスパーゼ
  • 受容体受容体
  • 酵素酵素
  • アポトーシス促進性アポトーシス促進性
  • 生存促進性生存促進性
  • GAP/GEFGAP/GEF
  • GTPaseGTPase
  • Gタンパク質Gタンパク質
  • アセチル化酵素アセチル化酵素
  • 脱アセチル化酵素脱アセチル化酵素
  • リボソームサブユニットリボソームサブユニット
  • 直接刺激型修飾直接刺激型修飾
  • 直接阻害型修飾直接阻害型修飾
  • 多段階刺激型修飾多段階刺激型修飾
  • 多段階阻害型修飾多段階阻害型修飾
  • 仮の刺激型修飾仮の刺激型修飾
  • 仮の阻害型修飾仮の阻害型修飾
  • サブユニットの分離または開裂産物サブユニットの分離または開裂産物
  • サブユニットの連結サブユニットの連結
  • 移行移行
  • 転写性刺激型修飾転写性刺激型修飾
  • 転写性阻害型修飾転写性阻害型修飾
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