novel concepts on cell death生化与分子细胞生物学系.pptVIP

Cell death: what’s new;细胞死亡 (Cell death);;?;程序性细胞死亡（PCD）指在生长发育过程中 细胞在基因调控下，按照一定时空顺序发生的 生理性死亡。 细胞凋亡是形态学的概念，程序性细胞死亡 是功能上的概念。;细胞凋亡的生物学意义; 1.形态学特征 (DNA染色、标记特征；电镜) 2.生化特征 （DNA电泳特征；caspase活性） 3.线粒体结构和功能的改变 （染料显示膜电位、cytoC） 4.质膜的改变 （Annexin V结合PS；PI结合DNA）;凋亡小体;生化特征 （1）胱冬肽酶级联反应及其在 凋亡中的作用 （2）DNA的降解 （3）ATP的消耗;胱冬肽酶（caspase）构成的级联反应 是凋亡过程的核心。 1）胱冬肽酶级联反应 2）胱冬肽酶的作用底物;返回;细胞凋亡的生化特征; 细胞凋亡的三种基本信号转导途径 （1）死亡信号途径 （2）线粒体途径 （3）内质网途径 （4）溶酶体途径 （酶漏出） ;Nat Rev Mol Cell Biol 2005;细胞凋亡的信号转导;Novel cell death mechanisms ?;Apoptosis: Is caspases required?;Nat Rev Mol Cell Biol 2005;CICD: Caspase-independent cell death;In vitro data indicated that TNF treatment alone induces the degeneration of the mitochondrial ultrastructure, possibly through the production of reactive oxygen species (ROS). Surprisingly, caspase inhibition actually sensitized mice to TNF treatment by increasing oxidative stress and mitochondrial damage in vivo. Mice that received a lethal TNF dose died about 24 hours post-injection; whereas pretreatment with a broad-spectrum caspase inhibitor, zVAD-fmk, induced rapid death within 4 hours20. Antioxidants blocked the sensitization of zVAD-fmk-treated mice to TNF-induced lethality, which indicated that ROS was responsible for cell death20. ;CICD vs tissue damage;Necrosis: A programmed cell death ?;The stereotyped features of apoptosis suggested that it would constitute a regulated cell death process, a notion that was elegantly shown in Caenorhabiditis elegans by the Horvitz laboratory in 1980–1990. Textbooks soon thought of apoptosis and necrosis as opposed mechanisms, necrosis being considered as a purely accidental and passive cell death subroutine. The first morphological classification of cell death was proposed by Schweichel and Merker4 who described, in rat embryos exposed to toxicants, type?I cell death associated with heterophagy, type?II cell death associated with autophagy and type?III cell death without digestion. Today, these cell death modes are referre