Chapter 13. Cell apoptosis. Extracellular cotrol of cell division, cell growth, and apoptosis. Mitogens stimulate G1-Cdk and G1/S-Cdk activities. 1090 –131= 959(cells). PRIZED Horvitz, and Sulston share Physiology or Medicine Nobel （ 2002 ）
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1090 –131= 959(cells)
PRIZEDHorvitz, and Sulston share Physiology or Medicine Nobel
“for their discoveries concerning genetic regulation
of organ development and programmed cell death”
A simplified model of one way that mitogens stimulate cell division
The cell division is cotrolled not only by extracellular mitogens but also by intracellular mechanisms that can limit cell proliferation.
Cell-cycle arrest or apoptosis induced by excessive stimulation of mitogenic pathways.
Activation of cell-surface receptors
Activation of PI 3-kinase
Activation of elF4E (translation initiation factor) and S6 kinase(phosphorylates ribosomal protein S6)
Increasing protein synthesis and cell growth
In development, homeostasis, tumor surveillance, and the function of the immune system.
Early : Chromosome condensation, cell body shrink
Later : Blebbing and Nucleus and cytoplasm fragment—
At last: Phagocytosed
B、Apoptosis: Apoptotic bodies
Biochemical characteristics of apoptosis:
180~200bp DNA ladder, Accumulation of tTG, PS flip-flop
by Cyto C
Lane 1．0 h
Death by apoptosis is a neat, orderly process
The Finding of CED3 mutant
Without losing any of their
cells to apoptosis.
CED3 gene play a crucial role in the process of apoptosis.
131 cells death.
C elegans: a millimeter long, transparent body only a few cell types, from zygote to mature adult only in 3.5days.
Mammalian: CED3 is related to mammalian interleukin-
1ß–converting enzyme (ICE or caspase-1)
a proteolytic system —caspase
(1) Why called caspase?
Active site: Cysteine
Cleavage site: Asparatic acid
Cysteine Asparatic acid specific protease
The cell responds to “death signals” that commit it to undergoing self-destruction.
The death sentence is carried out.
Apoptosis cells are recognized by phagocytes because they carry exposed markers, called “eat me” signals.
The best studied “eat me” signal is the presence of phosphatidylserine molecules in the outer leaflet of PM of apoptotic cells (by flop-flipase).
All caspases expressed as proenzymes— Procaspases
NH2-terminal prodomain: Highly variable
Large subunit (20kD)
Small subunit (10kD)
How are procaspases activated to initiate the caspase cascade?
The activation is triggered by adaptor proteins that bring multiple copies of specific procaspases.
3 groups of caspase:
1、apoptotic initiators: caspase-2, caspase-8, caspase-9 and caspase-10
2、apoptotic executioners: caspase-3, caspase-6 ，caspase-7 and 14 (morphology change)
3、inflammatory mediateors: caspase-1, and caspase-11
Procaspases are activated by binding to adaptor proteins
More than a dozen protein kinase, including FAK, PKC, and Raf1. FAK– disrupt cell adhesion for the apoptotic cell.
Lamins. Cleavage of lamins leads to the disassembly of the nuclear lamina and shrinkage of the nucleus.
Proteins required for cell structure. Such as IF, actin, and gelsilin. Cleavage and inactivation of these proteins lead to changes in cell shape.
Induce cell display signals marked it for phagocytosis .
The inhibitor of CAD (Caspase-activated Dnase, an endonuclease). Cleavage of CADinhibitor lead to activation of CAD, once activated, CAD translocates from the cytosol to the nucleus severing DNA into fragments.
Enzymes involved in DNA repair. Which are inactivated by caspase cleavage. DNA repair is a homeostatic activity that is inappropriate in an apoptotic cell.
Two principle pathways
(1)Extrinsic pathway: Fas Signaling Pathway
Receptor-mediated pathway of apoptosis
Fas (also called Apo-1 or CD95) is a member of the tumor necrosis factor receptor (TNFR) superfamily.
Bcl-2 Family(cytoplasmic factors):
Bad,Bid,and bax: promote apoptosis;
Bcl-X, Bcl-w,and Bcl-2: prevent apoptosis.
Internal stimuli: DNA damage, high Ca2+ , Oxidative stress
(2) Intrinsic pathway: Mitochondrial pathway
The mitochondria-mediated pathway of apoptosis
Various types ofcellular stress
Bcl-2 family: Bad or Bax to become inserted into OM of Mit
Release of cytochrome c from I-O space of Mit.
Form a multisubunit complex; and Caspase Cascade,…
Activation of caspase-2 is required for permeabilization of mitochondria, release of cytochrome c, and apoptosis
Pathways to cell death in C. elegans and mammals