apoptosis and diseases
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Apoptosis and Diseases. Contents. Concept Major pathways Key molecule s Apoptosis-related diseases Insufficient apoptosis in diseases Excessive apoptosis in diseases Coexistence of insufficient and excessive apoptosis in diseases Principles of treatment. History of Cell Death Research. - PowerPoint PPT PresentationTRANSCRIPT
Apoptosis and DiseasesApoptosis and Diseases
1. Concept 2. Major pathways 3. Key molecules4. Apoptosis-related diseases
• Insufficient apoptosis in diseases• Excessive apoptosis in diseases• Coexistence of insufficient and excessive
apoptosis in diseases5. Principles of treatment
ContentsContents
History of Cell Death ResearchHistory of Cell Death Research
Using C. elegan as a model
A highly regulated active cell death
characterized by cell shrinkage and
nuclear condensation.
pre-programed, cascade events ATP, gene expression
Morphology opposite to necrosis
Apoptosis or Programmed Cell DeathApoptosis or Programmed Cell Death
What is the difference of programmed cell death and apoptosis?
Apoptosis Necrosis
Nature Physiological or pathological; specific
Pathological, accidental
Stimulus Mild Strong
Biochemistry Active, energy-dependent, new protein synthesis
Passive, energy-independent, no protein synthesis
DNA
Morphology
Specific degradation, ladder (180-200 bp)
Intact, shrinkage, condensation
Random degradation
Lysis, swelling
Inflammation No Yes
Apoptotic body Yes No
Gene regulation Yes No
Apoptosis and NecrosisApoptosis and Necrosis
Initiation
Regulation
Execution
Phagocytosis
Physiological, e.g., growth factors, estrogen; virus; chemicals.
Inhibitory FactorsStimulatory FactorsPhysiological, FasL;Pathological, glutamate, free radicals;therapeutical, herb.
Conserved
Apoptotic ProcessApoptotic Process
Conserved apoptotic paradigms in C. elegans, Drosophia, and mammals
• Death receptor-mediated apoptotic pathway
• Mitochondria-mediated apoptotic pathway
• Nuclear-mediated apoptotic pathway
Apoptotic PathwaysApoptotic Pathways
death-inducing signaling complex
Fas-associating protein withdeath domain
Apoptotic PathwaysApoptotic Pathways
Mitochondrial Membrane Permeabilization (MMP) in Apoptotic Process
Mitochondrial Membrane Permeabilization (MMP) in Apoptotic Process
ER and ApoptosisER and Apoptosis
Cross-talking among Organelles and Molecules in Apoptosis
1. Activation of endonuclease
2. Activation of caspases
DNA ladder
Collapse of cell and nucleus
Executors Executors
Role of Endonuclease180-200 bp
H1ZnZn2+
CaCa2+ MgMg2+
Endonuclease
Role of Caspases
(Focal adhesion kinase)
(p21-activated kinase 2)
(Ste20-related kinase)
Phosphatidylserine (PS) receptor (PSR) acts as a ‘tickle’ receptor for uptake of apoptotic cells
2. Bcl-2 family : anti-apoptotic: Bcl-2 (B cell lymphoma/leukemia), Bcl-XL
pro-apoptotic: Bax, Bad
Key MoleculesKey Molecules
1. Caspases: Caspase-3,Caspase-8,Caspase-9, etc.
3. Others: Apaf-1(apoptosis activating factor-1), cytochrome C, IAPs, p53, etc.
Table 1. Caspase-deficient miceKnockout Phenotype
Caspase-1 Viable; impaired processing of IL-1; resistant to endotoxic shock. Caspase-2 Viable; excess numbers of female germ cells; oocytes resistant to chemotherapeutic drugs; B lymphoblasts resistant to granzyme B; accelerated death of facial neurons during development and of sympathetic neurons deprived of NGF.Caspase-3 Lethality at 3–5 weeks of age; defective neuronal apoptosis; T cells resistant to antigen-induced death; abnormal apoptotic morphology in dying cells.Caspase-8 Lethality around E12.5; hyperemia and abnormal heart muscle development; MEFs resistant to TNF, Fas and DR3 but sensitive to UV irradiation, etoposide, staurosporine, serum deprivation.Caspase-9 Perinatal lethal; impaired neuronal apoptosis; ES cells, MEFs and thymocytes generally resistant to intrinsic death stimuli such as DNA damage, though resistance depends on cell type.Caspase-11 Viable; impaired processing of caspase-1, IL-1; resistant to endotoxic shock. Caspase-12 Viable; embryonic fibroblasts are resistant to ER stress.
Apoptosis-related DiseasesApoptosis-related Diseases
Growth Apoptosis
Balance of Growth and ApoptosisBalance of Growth and Apoptosis
Autoimmune disease,Tumor, virus infection, etc
Proliferation
Apoptosis
Insufficient Apoptosis in DiseasesInsufficient Apoptosis in Diseases
(1) Tumor Pathogenesis for tumor:
stimulated cell proliferation inhibited cell apoptosis
Cell survival > cell death in diseased tissue
Etiologically, cell apoptosis is actually one of the natural anti-carcinogenic mechanisms
(2) Autoimmune diseases
The lesion is caused by attack of auto-antibody or sensitized T cell to self-antigen.
Normally, T cells against auto-antigen are eliminated by apoptosis during the development.
When the negative selection is deregulated
(thymus diseases), T cells survive and abnormally proliferate, then attack self tissue, lead to autoimmune diseases.
Mechanism of autoimmune diseases — Disrupted apoptosis of self-reactive cell
Point mutation of FasL
Insertion mutation of Fas
Structural abnormity of FasL
Decreased expression of Fas protein
Escape the negative selection of self-reactive
T cells
Autoimmune diseases
Rheumatoid arthritis
It is caused by decreased apoptosis and increased proliferation of arthral cell ;
Increased IL-1 and TGF-β1 and decreased Fas expression, which inhibit apoptosis;
Increased Bcl-2 、 Bcl-XL, which increased the threshold of apoptosis;
Resistance of T-cells to apoptosis.
AIDS, neurodegenerative diseases, aberrant
myocardial ischemic-reperfusion
Excessive Apoptosis in DiseasesExcessive Apoptosis in Diseases
( 1 ) Acquired Immune Deficiency Syndrome —AIDS
HIV infection increased Fas gene expression
gp120glycoprotein expression + receptor in CD4 lymphocyte
infusion of infected CD4 cell leads to syncytin formation
produce tat protein (enhance Fas expression) secret TNF
CD+4T- lymphocyte apoptosis
AIDS
(2) Cardiovascular diseases
Cell death induced by ischemia-reperfusion Apoptosis Necrosis Early stage Later stage Peripheral region of infarct Center of infarct Mild ischemia Severe ischemia Chronic Acute
Possible mechanism (myocardial cell apoptosis
induced by ischemia-reperfusion): (1) oxidative stress; (2) calcium overload; (3) p53 gene activation;
(4) death receptor Fas, TNF over expressed.
Cardiovascular diseases (cont.)
Cardiovascular diseases (cont.)
Heart failure: Myocardial cell diminishes in pressure- overload-induced heart failure
Possible mechanisms: Oxidative stress; cytokines; ischemia; hypoxia; pressure or volume overload, neural-endocrine system deregulation;
Lead to myocardial cell apoptosis
Alzheimer disease , Parkinson disease , Huntington disease , multiple
sclerosis
Factors involved in neuronal apoptosis:
amyloid peptide, calcium overload,
oxidative stress and neuronal growth factor
insufficiency, etc.
Lead to neuronal cell apoptosis
( 3 ) Neurodegenerative diseases
Coexistence of Excessive and Insufficient Apoptosis in Diseases
Coexistence of Excessive and Insufficient Apoptosis in Diseases
oxidative LDL
platelet activation Ag Ⅱ
hypertension
excess apoptosis insufficiency in in endothelium smooth muscle
atherosclerosis
Coexistence of Excessive and Insufficient Apoptosis
Diseases Mechanism Apoptosis
Heart failure Ischemia, inflammation, etc.
AIDS HIV infection of T4 cell
AD, PD Ischemia, inflammation, etc
Cancer P53, Bcl-2
Autoimune diseases Autoreactive T cells or B cells
Atherosclerosis Endothelial cell, muscle cell
Apoptosis and DiseasesApoptosis and Diseases
Gene Affected diseaseTumor necrosis factor Familial periodic fever syndrome receptor 1 (TNF-R1)Fas (CD95; Apo-1) Autoimmune lymphoproliferative syndrome type I(ALPS I), malignant lymphoma, bladder cancerFas ligand Systemic lupus erythematodes (only one case identified)Perforin Familial hemophagocytic lymphohistiocytosis (FHL)Caspase 10 Autoimmune lymphoproliferative syndrome type II (ALPS II)
bcl-10 Non-Hodgkin’s lymphomap53 Various malignant neoplasmsBax Colon cancer; hematopoetic malignanciesbcl-2 Non-Hodgkin’s lymphomac-IAP2 Low-grade MALT lymphomaNAIP1 Spinal muscular atrophy
Apoptosis Genes mutated in DiseasesApoptosis Genes mutated in Diseases
Principle of TreatmentPrinciple of Treatment
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