Cellular apoptosis and disease

Zhao Mingyao

BMC.ZZU

Background knowlege

Concept of apoptosis

autonomic and ordered cell death controlled by gene or called as programmed cell death (PCD)

nematode

drosophila mouse

research model

• Nematode : total 1090 cells in young, 959 cells in adult, 131 cells lost ?

• Time : 1 h r • Gene : 14 gene known

Classical Apoptosis model

1.Differences between necrosis and apoptosis

Apoptotic bodies溶酶释出，

炎症反应

ATPATP(-)

Passive

Active new protein

Strong stimulation

Weak ~

?

Comparison between apoptosis & necrosis

2.The biological meanings of apoptosis

By the time I was born, more of me had died than survived. It was no wonder I cannot remember; during that time I went through brain after brain for nine months, finally contriving the one model that could be human, equipped for language.

In humans, as many as 1011 cells die in each adult each day and are replaced by other cells. The mass of cells we lose each year is close to our entire body weight!

①Maintain normal development and growth:remove excess cell

② Maintain homeostasis : remove damaged, mutant , senile cell

③Active defense function: block replication of cells infected by virus

Apoptosis importance

3. apoptosis process (period)

Course of cellular apoptosis

1.Transduction of apoptosis signal

starting signal Ca2+ 、 cAMP 、 ceramide

2. Activation of apoptosis gene

express enzymes and other substance

3. Execution of cellular apoptosis

DNase and Caspases

4. Removal of apoptotic cell engulfed by near cell ( Mφor other cell )

TSP

TSP: thrombospondin

4.The two major biochemical changes in the courses of apoptosis

(1)Endogenous Dnase activation and its effect

• A series cellular ST activation

• Execution of chromosome DNA cleavage

Fragment of DNA ： classic ladder pattern ？

300 kb pieces

50kb

180~200bp or its

whole folds fragment

5min

90min

Endonucleases first cleave

chromosome caspase-activated deoxyribonucleaus

poly (ADP-ribose)polymerase

–

+necrosis apoptosis

famous nucleosomal ladder

DNA electrophoresis

(2) Caspases activation and its effect

A group of protease ( 13 members )cysteine-containing aspartate-spicific protease

caspases

note:Cysteine 半胱 aa Aspartate 天冬 aa

Structure and classification of procapases

Caspases function

① Deactivating inhibitor of apoptosis: as Bcl-2

② Hydrolyzing proteoin structure, cellular decomposing, apoptotic body

③ Hydrolyzing the related active proteins : make them to gain or lose function

Apoptosis signal pathway

1. Death receptor pathway

Inducing factor →ΔΨm↓

PTP

permeability↑→apoptosis starting factor （ Cyt. C ， Apaf ， AIF ） released

Abbreviation note:

•PTP----permeability transition pore

•Apaf----apoptosis protease activated factor

•Cyt.C----cytochrome C

•AIF---- apoptosis inducement factor

2. Mitochondrial pathway

3. 3. Endoplasmic reticulumial pathway

Regulators of apoptosis

1. Bcl-2 family pro in apoptosis

• Bcl-2, Bcl-XL, Mcl-1 promote survival

(anti-apoptotic pro)

• Bax, Bad, Bak, Bid induce death

(pro-apoptotic pro)

cell

bcl-2 function

• Binding Apaf-1

• Prevent release of Cyto C

• Regulator of Ca2+ homeostasis

• Antioxidant

2. IAP in apoptosis

• (IAP)/BIRP gene family: XIAP, c-IAP-1, c-IAP-2, ILP-2, NAIP, Livin and Apollon

• Block apoptosis

inhibit initiator and effector caspases

( proteolytic processing and enzymatic activity)

BIRC # for "baculoviral IAP repeat-containing".

IAP: inhibitor of apoptosis protein

The "Inhibitor of Apoptosis Proteins" family

Characterization of IAP family members

• BIRC1 (Neuronal apoptosis inhibitory protein; NAIP)

• BIRC2 (API1; HIAP2; cIAP1; MIHB)

• BIRC3 (API2; HIAP1; cIAP2; MIHC)

• BIRC4 (XIAP; API3; MIHA; ILP)

• BIRC5 (Survivin; API4; TLAP)

• BIRC6 (Apollon; BRUCE)

• BIRC7 (MLIAP; KIAP; Livin)

• BIRC8: (ILP-2; TIAP)

3. Apoptosis Inhibitory factor cytokine— IL-2 ， NGF

hormone— ACTH 、 testosterone , estrogen other— Zn2+(zinc), phenobarbital , Cysteine

protease inhibitor, EB virus, neutroamino acid

4. Inducers of apoptosis

Apoptosis induced by death signal:

hormone, GF↑↑, GC

physic and chemic factor

immune

microbe

TNFa, Fas

Adaptor (FADD,TRADD)

Caspase 8

NGF NGF+Ceramide 24h

PC12 cell

Condensed and fragmented nuclei of dead cells

5. Oxidative stress induce apoptosis

• P53 gene activation

• activating Ca2+/Mg2+ -dependent Dnase

• Ca2+ influx↑

• activating NF-κB and Ap-1 （ Fas)

G1

S

G2

M

Cyclin A+CDK

Cyclin A+CDK1

Cyclin B

Cyclin D

p53

Bax+ Bcl-2↓

molecular policeman?

Blocking IGF+R

6. P53 in apoptosis

7. [Ca2+] dyshomeostasis

• activating Ca2+/Mg 2+ -dependent Dnase

• activating nuclear transcription factor related to apoptosis

• Ca 2+ promoting to exposing enzymolytic sites between nuclear nuleosomes

Some diseases related to apoptosis

1. Tumor and apoptosis

insufficiency of apoptosis• Bcl-2 express↑• P53 mutation or loss

2. Immune diseases and apoptosis

(1) Autoimmune diseases

• Hashimoto’s thyroiditis (HT, chronic lymphocytic thyroiditis ) : Fas/FasL mediated apoptosis

• SLE (Systemic lupus erythematosus)

•SLE (Systemic

• lupus erythematosus)

(2)AIDS

HIV CD4+ cell damaged selectively

3. Heart failure and apoptosisapoptosis

myocyte hypertrophy and widening of interstitial spaces due to deposition of collagen, inflammatory cells and amyloid.

4. Atherosclerosis and in apoptosis

Insufficiency and excess of apoptosis exist together

oxLDL ↑

activated plt ↑

Ag II

hypertension

Endothelia barrier↓

Endothelia ~↑

Smooth ~ insufficiency

(proliferation↑>apoptosis↑ ）

Neuron retrogression—— loss of neuron in

hippocampus and  basal nuclei

• Loss of Cholinergic neurons reachs 30%~50% ， involved cortex

5. Alzheimer disease and apoptosis

AD mechanism

disease cause such as OFR

Ca2+ inward flowing↑

activating related genes

neuron

promoting β- amyloid content ↑

Tan pro overphosphorylation

Regulating apoptosis in treating diseases

Regulating apoptosis in treating diseases

• Interfere or promote apoptosis

• Molecular targets

bociwana

Jibuti

erlitiya

ZZU in China

Class, day, year

Thanks!