Abnormal Cell Proliferation,Differentiation Abnormal Cell Proliferation,Differentiation Apoptosis and Related DiseaseApoptosis and Related Disease

Department of PathophysiologyDepartment of Pathophysiology

Shanghai Jiao-Tong University School of MedicineShanghai Jiao-Tong University School of Medicine

Evan, GI and Vousden, K. (2001) Nature 411:342

The Cancer Problem

Proliferation Differentiation

Apoptosis

Cell

【【 Cell ProliferationCell Proliferation 】】 Cell proliferation is a process of cell division and regeneration, Cell proliferation is a process of cell division and regeneration, which results in an increase in the cell number with exact passages which results in an increase in the cell number with exact passages of genetic information to their daughter cells.of genetic information to their daughter cells.

Abnormal Cell Proliferation and DiseasesAbnormal Cell Proliferation and Diseases

Phase of cell cycle

• M-Phase– Mitosis– Cytokinesis

• Interphase– G1 = Gap between M and S– S = Synthesis (DNA and cen

trosomes replicated)– G2 = Gap between S and M

Interphase Prophase Prometaphase Metaphase

Anaphase Telophase Cytokinesis

Mitosis

2001 Nobel Prize

Leland H. Hartwell 1970s“Checkpoint”Yeast genetics~100 CDC genesStart gene

Tim Hunt 1980sCyclinsSea Urchins

Paul M. Nurse1970sCDKsyeast

Cell Cycle Regulation

• Cyclins

• Cyclin Dependent Kinases (CDKs)

• Cyclin Dependent Kinases Inhibitors (CDKIS)

●●CyclinCyclin

【【 Classification Classification 】】

Cyclin B1Cyclin B1 、、 Cyclin ACyclin A 、、 Cyclin ECyclin E 、、 Cyclin DCyclin D11,D,D22,D,D33. . FF,,G,H,TG,H,T. .

Cyclin Protein kinase process regulated

Cyclin D1-3 Cdk 4,6 G1-phase progression

Cyclin E Cdk2 G1 to S-phase

Cyclin A Cdk2 S-phase progression

Cyclin A Cdk1 S through G2

Cyclin B Cdk1 M-phase

Cyclic Degradation:

Ubiquitin-mediated breakdown by Proteasome

Experimental Demonstration that Cyclin D is Required for Passage Through the Restriction Point in the Mammalian Cell

【【 CDKCDK11 activates cell cycle activates cell cycle 】】

CDKCDK11activationactivation

Cyclin BCyclin B binds binds CDKCDK11

phosphorylation of CDKphosphorylation of CDK1 1 byby CAKCAK

Cell cycleCell cycle

●●CDKs CDKs

CDKs are group of serine and threonine kinases.CDKs are group of serine and threonine kinases.

Thr14 、 Tyr15 dephorsphorylation

CDK activation kinasekinase (CAK)

【【 CDK activation and cell cycle regulationCDK activation and cell cycle regulation 】】

▲ ▲ CDKCDK22 binds cyclin E binds cyclin E ， ， CDKCDK

44 、、 CDKCDK6 6 binds cyclin Dbinds cyclin D

11 、、 DD22 、、 DD33

pRb phosphorylation E2F release↑ pRb phosphorylation E2F release↑ initiate G1 phase initiate G1 phase

▲▲CDKCDK22 binds cyclin E and A recognize chromosome ARS binds cyclin E and A recognize chromosome ARS

Accelerate S phaseAccelerate S phase

▲▲CDKCDK11 binds cyclin B binds cyclin B

1 1 initiate M phaseinitiate M phase

▲▲CDKCDK11 binds cyclin A binds cyclin A initiate Ginitiate G

22 phase phase

DNA synthesis DNA synthesis initiate S phaseinitiate S phase

【【 mechanism of inhibitionmechanism of inhibition 】】

▲ CDIs direct bind the phosphorCDIs direct bind the phosphor

ylation site of CDK-cyclin complylation site of CDK-cyclin compl

ex.ex.

▲ P16P16INK4a INK4a binds CDK4, inhibits itbinds CDK4, inhibits it

s interaction with cyclins.s interaction with cyclins.

●●CDICDI

▲Ink4Ink4 ：： P16P16INK4aINK4a 、、 P15P15INK4bINK4b 、、 P18P18INK4cINK4c 和和 P19P19INK4d INK4d CDKCDK44 、、 CDKCDK

66

▲Cip/KipCip/Kip ：： p21p21CiplCipl 、、 P27P27Kip1Kip1 和和 P57P57Kip1Kip1 CDKCDK22

【【 Check mechanismCheck mechanism 】】

●●P53P53 ：： In response to DNA damage in G1, the protein level of p53 rises dramatica

lly due to the activation of a checkpoint protein kinase (chk2) that phosphorylate p53

and make it less susceptible to degradation by the ubiquitination/proteasome pathway.

This enables p53 to activate transcription of the cdk inhibitor (CKI) p21 which binds

to all cdks and inhibits their action and thus “arrests” the cells until the DNA damage

can be repaired.

■ ■Checkpoint of cell cycleCheckpoint of cell cycle ）） DNA damage DNA damage GG11/S/S

CheckpointCheckpoint DNA replication DNA replication S/GS/G22

spindle assembly spindle assembly GG22/M/M

G1 phase S phase

CDK

Growth Signal

cyclin/

DNA damage, other insults

p53

p21

Abnormal proliferation differentiation related diseaseAbnormal proliferation differentiation related disease

abnormal proliferation abnormal differentiation abnormal proliferationabnormal proliferation abnormal differentiation abnormal proliferation

and differentiationand differentiation

aplastic anemia obesity malignant tumor

leucoderma heritage hemoglobinopathy psoriasis

prostatic hypertrophy muscular dystrophy dysembryom

scleratheroma congenital deformity

Familial erythrocytosis X-linked hyper IgM syndrome

►►Abnormal cell cycle & diseasesAbnormal cell cycle & diseases

Deregulation of cell cycle causes cell proliferation excessive or insufficDeregulation of cell cycle causes cell proliferation excessive or insufficency.ency.

【【 Deregulation of cell cycleDeregulation of cell cycle 】】

■■loss of control in driving cell cycle progression(Cyclin,CDK,CDIloss of control in driving cell cycle progression(Cyclin,CDK,CDI ））■■The impairment of checkpoint systemThe impairment of checkpoint system

Malignant tumorMalignant tumor

Cancer is a disease where regulation of the cell cycle goes

awry and normal cell growth and behavior is lost .

11 ． ． loss of control in driving cell cycle progressionloss of control in driving cell cycle progression

■ ■ Overexpression of cyclinsOverexpression of cyclins

【【 Cyclin DCyclin D1 1 overexpressionoverexpression 】（】（ oncogeneoncogene ））

▲gene amplificationgene amplification （（ major reasonmajor reason ） ）

Observed in breast, gastric, esophageal cancer.Observed in breast, gastric, esophageal cancer.●●Chromosome rearrangementChromosome rearrangement

Cyclin DCyclin D11 gene under the control of parathyrin promotergene under the control of parathyrin promoter

Synthesis of Cyclin DSynthesis of Cyclin D11 increase Parathyroid carcinoma increase Parathyroid carcinoma

●●Chromosome translocationChromosome translocation

t(11:14) (q13:q32)t(11:14) (q13:q32)

Cyclin DCyclin D1 1 gene under the control of Ig heavy chain gene enhancergene under the control of Ig heavy chain gene enhancer

Cyclin DCyclin D11 overexpression overexpression

■■ abnormal expression of CDKabnormal expression of CDK

Mainly observed in CDKMainly observed in CDK44 、、 CDKCDK

66 overexpression. overexpression.

CDKCDK44↑+ cyclin D binding↑ CDK↑+ cyclin D binding↑ CDK

44/cyclin D↑ CDKs expression↑ /cyclin D↑ CDKs expression↑

pRb pRbphosphorylation↑ cell over proliferationpRb pRbphosphorylation↑ cell over proliferation

E2F ↑ GE2F ↑ G11/S transition accelerated/S transition accelerated

【【 mechanism of Cyclin D in tumorgenesismechanism of Cyclin D in tumorgenesis 】】

Cyclin D overexpression + cytokinesCyclin D overexpression + cytokines

CDKs water fall effect↑ cell over proliferation susceptible to cancerizatioCDKs water fall effect↑ cell over proliferation susceptible to cancerizatio

n n

▲gene mutationgene mutation

Cyclin DCyclin D1 1 TT

286286mutation Cyclin Dmutation Cyclin D1 1 ubiquitination block Cyclin Dubiquitination block Cyclin D

11↑↑

■ ■ CDI insufficency and mutationCDI insufficency and mutation

▲ InK4 inactivationInK4 inactivation

【【 causes of p16 causes of p16 InK4InK4 inactivation inactivation 】】

mutation or deletion, chromosome translocation, hypermethylation.mutation or deletion, chromosome translocation, hypermethylation.

【【 MechanismMechanism 】】

p16p16 InK4 InK4 gene expression↓ CDK gene expression↓ CDK44/cyclin D binding↓/cyclin D binding↓

cell susceptible to proliferationcell susceptible to proliferation

susceptible to tumorgenesissusceptible to tumorgenesis

【【 MechanismMechanism 】】

p53 mutation P21p53 mutation P21cip1 cip1 transcription↓ DNA damage cell↑transcription↓ DNA damage cell↑

▲ Deficient expression of Kip/CipDeficient expression of Kip/Cip

P21P21cipl cipl function cyclins/CDKs activity↓ cell cyclefunction cyclins/CDKs activity↓ cell cycle

PCNA DNA replication block PCNA DNA replication block

2. Impairment of checkpoint system2. Impairment of checkpoint system

main reasonmain reason ：： GG11/S/S 、、 GG22/M checkpoint dysregulation/M checkpoint dysregulation

consequenceconsequence ：： function of detect DNA damagefunction of detect DNA damage

Table 8.3 The Biology of Cancer (© Garland Science 2007)

Table 8.4 The Biology of Cancer (© Garland Science 2007)

▲P53 mutation or loss susceptible to cancergenesisP53 mutation or loss susceptible to cancergenesis

mutagenmutagen

checkpoint function↓ genetic instability replication fidelity↓checkpoint function↓ genetic instability replication fidelity↓

■ ■GG11/S transition dysregualtion /S transition dysregualtion

▲P53 enter S phaseP53 enter S phase

DNA damage successfulDNA damage successful

GG11/S check G/S check G11 arrest DNA repair arrest DNA repair

failurefailure

apoptosis bcl-2 bax P53apoptosis bcl-2 bax P53

Table human tumor p53 gene mutation hotspot and frequencyTable human tumor p53 gene mutation hotspot and frequency

tumor frequencytumor frequency （（ %% ） ） hotspot tumor frequencyhotspot tumor frequency （（ %% ） ） hotspothotspot

Lung cancer 56 157Lung cancer 56 157 ，， 248248 ，， 273 prostatic caner 30 unknown273 prostatic caner 30 unknown

Colon carcinoma 50 175,245,248,273 hepatocellular carcinoma 45 249Colon carcinoma 50 175,245,248,273 hepatocellular carcinoma 45 249

Esophageal carcinoma 45 unknown colloid carcinoma 25 175,248Esophageal carcinoma 45 unknown colloid carcinoma 25 175,248

Ovarian cancer 44 273 breast cancer 22 175,248,273Ovarian cancer 44 273 breast cancer 22 175,248,273

Pancreatic cancer 44 273 endometrial cancer 22 248Pancreatic cancer 44 273 endometrial cancer 22 248

Skin cancer 44 248Skin cancer 44 248 、、 278 thyroid cancer 13 248,273278 thyroid cancer 13 248,273

Gastric cancer 41 unknown Gastric cancer 41 unknown leukemia 12 175,248leukemia 12 175,248

Head and neckHead and neck

squamous cell carcinoma 37 48 uterine cervix cancer 7 273squamous cell carcinoma 37 48 uterine cervix cancer 7 273

Bladder cancer 34 280 soft tissue sarcoma 31 unknownBladder cancer 34 280 soft tissue sarcoma 31 unknown

DNA virus: SVDNA virus: SV4040 、、 HPVHPV 、、 adenovirus P53 inactivationadenovirus P53 inactivation

■■ impairment of Gimpairment of G22/M checkpoint /M checkpoint

GG22/M transition/M transition

DNA double strand breakDNA double strand break

activation of DNA damage checkpoint block cell enter M phaseactivation of DNA damage checkpoint block cell enter M phase

induce repair gene transcriptioninduce repair gene transcription

DNA repairDNA repair

▲loss of Gloss of G22/M checkpoint chromosome rearrangement, loss/M checkpoint chromosome rearrangement, loss

Primary ThrobocythemiaPrimary Throbocythemia

■ ■ clinical clinical symptomssymptoms ：： is characterized by a platelet count greateis characterized by a platelet count greater than 600,000/µL, megakaryocytic hyperplasia, splenomegaly, r than 600,000/µL, megakaryocytic hyperplasia, splenomegaly, and a clinical course complicated by thrombotic and/or hemorrhand a clinical course complicated by thrombotic and/or hemorrhagic episodesagic episodes.

■■ The cause of ET is not fully understood. About half of patients with ET have a mutation of the JAK2 (Janus kinase 2) gene in their blood cells. Whether or not a patient has the mutation does not appear to affect the nature or course of the disease. Research is under way to determine the precise role of JAK2 mutations and to identify other mutations in ET patients.

Apoptosis is a genetically controlled process regulated by complApoptosis is a genetically controlled process regulated by complex molecular signaling systems.ex molecular signaling systems. It is also known as cellular self destruction or cell-suicide or programmed cell death (PCD).

【【 Concept of apoptosisConcept of apoptosis 】】

【【 physiology implicationphysiology implication 】】

■ ■ is involved in tissue developmentis involved in tissue development

■ ■ maintain the homeostasismaintain the homeostasis

■■is involved in defense responseis involved in defense response

Apoptosis and DiseasesApoptosis and Diseases

“for their discoveries concerning genetic regulation

of organ development and programmed cell death”

1090 –131= 959(cells)

Robert Horvitz John Sulston Sydney Brenner

Physiology or Medicine Nobel Prize 2002

■ ■ loss of contact with neighbering cellsloss of contact with neighbering cells

■■Blebbing of cell membraneBlebbing of cell membrane

■■Condensation of chromatinCondensation of chromatin

■■Apoptotic bodiesApoptotic bodies

apoptotic cell (SEM) (TEM)APLAPL ApoptosisApoptosis

1. The morphologic characteristics of apoptosis1. The morphologic characteristics of apoptosis

Features Features of apoptosis cellsof apoptosis cells

Morphological features of Morphological features of apoptosisapoptosis

Membrane blebbing

11 ）） DNA ladding patternDNA ladding pattern

activation of endonuclease activation of endonuclease

cleave DNA at specific sites between nucleosomescleave DNA at specific sites between nucleosomes

oligonucleosomal fragmentsoligonucleosomal fragments （（ 160160 ～～ 200bp interval200bp intervalss ））

2. The biochemical characteristics of apoptosis2. The biochemical characteristics of apoptosis

22 ）） Phosphatidylserine externalization

33 ）） activation of caspase and its functionactivation of caspase and its functionCaspase (cysteine-containing aspartate-specific protease)

Stimuli of apoptosisStimuli of apoptosis

TableTable ：： effects of various factors on apoptosiseffects of various factors on apoptosisInducers Inhibitors

Physical and chemical factors

Irradiation, high temperature, stress, chemotherapeutic drugs

cytokines IL-2 、 NGF

Hormone and cytokines

Glucocorticoid, TNF

hormone ACTH, testosterone, estrogen

Immunity granzyme others Zn2+ 、 agrypnal 、 cystein protease inhibitor, EBV, cowpox, virus, neutral amino acid

pathogen HCV, HIV

Caspase-dependent apoptosisCaspase-dependent apoptosis

（（ 11 ） ） Concept, Classification, Construction of CaspasesConcept, Classification, Construction of Caspases

■ ■ Caspase belong to cystein proteasesCaspase belong to cystein proteases

Mechanism of apoptosisMechanism of apoptosis

■ ■ Caspase categoriesCaspase categories

upstreamupstream （（ Caspase-8 , -9, -10Caspase-8 , -9, -10 ））

downstreamdownstream （（ Caspase -2, -3,-6,-7Caspase -2, -3,-6,-7 ）（）（ common pathwaycommon pathway ））

▲ Caspase Caspase

（（ Ced-3 subfamilyCed-3 subfamily ））

Death receptor pathwayDeath receptor pathway

Mitochondrial pathwayMitochondrial pathway

Interaction of large and small subunit （ dimer ）

caspase activation （ tetramer ）

■■ Caspase activationCaspase activation

Pro-caspase ： NH2 terminal domain 、 20KD subunit 、 10KD subunit

cleavage

1. Extrinsic or cytoplasmic pathway1. Extrinsic or cytoplasmic pathway

■■Death receptor TNFR, FasR, DRDeath receptor TNFR, FasR, DR33,, DRDR44,, DRDR55,,The DR family is part of the tumor necrosis factor receptor superfamily. Triggering members of the DR family by death ligands results in the transduction of either apoptotic or survival signals.

■■pathwaypathwayFSAL

FADDFADD

Pro-caspase-8Pro-caspase-8

Caspase-8Caspase-8

Caspase-3Caspase-3Pro-caspase-3Pro-caspase-3

Growth factors, Fas antibodyGrowth factors, Fas antibody

FasR

FADDFADD （（ Fas-associated death domainFas-associated death domain ）； ）； DDDD （（ death domaideath domainn ）；）；

DED DED （（ death effector domaindeath effector domain ）。）。

DEDDED DEDDED

DDDD

apoptosis

2.2. Intrinsic or mitochondrial pathwayIntrinsic or mitochondrial pathway

CaCa2+2+

NONO

hypoxiahypoxia

ROSROS

stressstress

Bid Caspase-8Caspase-8

MMP↑MMP↑ 、、 swellingswelling 、△、△ m↓m↓

Apaf-1activationApaf-1activation

Cyt.cCyt.c

MPT openMPT open Cyt.cCyt.c

+

Pro-caspase-9Pro-caspase-9Caspase-9Caspase-9

ATPATP

Apaf-1Apaf-1++

Apaf-1activationApaf-1activation

Cyt.cCyt.c

CARDCARD

ApoptosomeApoptosome AIFAIF

caspase-independent apoptosis

Pro-Caspase-3Pro-Caspase-3Caspase-3Caspase-3

apoptosis

Pro-caspase-2Pro-caspase-2caspase-2caspase-2

Pro-caspase-6Pro-caspase-6 Caspase-6Caspase-6

Pro-caspase-7Pro-caspase-7 caspase-7caspase-7

Pro-caspase-9Pro-caspase-9

ICADICADCADCAD

DNA cleavageDNA cleavage apoptosisapoptosis

Cleavage of Cleavage of structural proteinstructural protein

caspase-9caspase-9

3.3. Activation of caspase-3 (Effector caspase)Activation of caspase-3 (Effector caspase)

Caspase-3Caspase-3

Pro-caspase-3Pro-caspase-3

Non-Caspase dependent apoptosisNon-Caspase dependent apoptosis

■■calcium overloadcalcium overload

Activation of Ca/MgActivation of Ca/Mg2+2+dependent endonucleasedependent endonuclease ，， DD

NA cleavageNA cleavage ；； activation of transglutaminase, apoptotic activation of transglutaminase, apoptotic

bodies.bodies.

■■AIFAIF

TNF-αTNF-α 、、 CDCD33-Ab-Ab 、、 TCDDTCDD

Plasma [CaPlasma [Ca2+2+] ↑] ↑

■■activation of Caactivation of Ca2+2+/Mg/Mg2+2+dependent endonucleasedependent endonuclease ，， DNA cleavageDNA cleavage ；；

■■activation of activation of transglutaminase, transglutaminase, wide cross-linking of cytoskeleton.wide cross-linking of cytoskeleton.

■■transcription of apoptosis related genetranscription of apoptosis related gene ；；

■ ■ mitochondrial dysfunctionmitochondrial dysfunction

Mechanism of calcium overload Mechanism of calcium overload induced apoptosisinduced apoptosis

apoptosis

Mechanism of apoptosisMechanism of apoptosis

11 ．． Oxidation damage Oxidation damage

Oxygen free radicals disrupt the normal redox equilibrium, result in the Oxygen free radicals disrupt the normal redox equilibrium, result in the injuring of protein,lipid and DNA.injuring of protein,lipid and DNA.

【【 MechanismMechanism 】】

Activation of Activation of p53, consuming of ATP, membrane lipid peroxidation, acp53, consuming of ATP, membrane lipid peroxidation, activation of endonuclease, initiating apoptosistivation of endonuclease, initiating apoptosis ..

22 ．． Calcium overloadCalcium overload

33 ．． Mitochondria damage Mitochondria damage

Table 1 apoptosis regulatorsTable 1 apoptosis regulators

function genefunction gene

inhibitors Bcl-2 Bcl-Xinhibitors Bcl-2 Bcl-XLL 、、 A1/Bfl-1A1/Bfl-1 、、 Bcl-wBcl-w 、、 Bcl-G and Mcl-1Bcl-G and Mcl-1

activators P53activators P53 、、 BaxBax 、、 BadBad 、、 BakBak 、、 BidBid 、、 BimBim 、、 BikBik 、、 BoBo

kk 、 、

Bcl-BBcl-B 、、 Bcl-XsBcl-Xs 、、 KrkKrk 、、 MtdMtd 、、 Nip3Nip3 、、 NixNix 、、 NoxNox

aa

Dual regulators c-mycDual regulators c-myc 、、 Bcl-xBcl-x

Regulators of apoptosisRegulators of apoptosis

Bcl-2

■■ Bcl-2Bcl-2 （（ Bcl-XBcl-XLL ）） inhibit MPT openinhibit MPT open ，， Cyt.c Cyt.c 、、 AIF release↓AIF release↓

■■ Bcl-2 binds cyt CBcl-2 binds cyt C

■■ Bcl-2 binds and inactivates Apaf-1Bcl-2 binds and inactivates Apaf-1 ，， blocks caspase-9 activationblocks caspase-9 activation

11 ．． Bcl-2 Family & regulating functionsBcl-2 Family & regulating functions

MMP↑MMP↑ 、、 swellingswelling 、△、△ m↓m↓

Apaf-1activationApaf-1activation

Cyt.cCyt.c

MPT openMPT open Cyt.cCyt.c

+

Pro-caspase-9Pro-caspase-9Caspase-9Caspase-9

ATPATP

Apaf-1Apaf-1++

Apaf-1activationApaf-1activation

Cyt.cCyt.c

CARDCARD

ApoptosomeApoptosome AIFAIF

caspase-independent apoptosis

Pro-Caspase-3Pro-Caspase-3Caspase-3Caspase-3

apoptosis

【【 MechanismMechanism 】】

■■ Downregulates the expression of Bcl-2.Downregulates the expression of Bcl-2.

■■ P53 induces Bax, NOXA, PUMA expression.P53 induces Bax, NOXA, PUMA expression.

■■ P53 induces Fas expression.P53 induces Fas expression.

■■ P53 relocalizes Fas to cell membrane.P53 relocalizes Fas to cell membrane.

22 ．． pp5353 （（ tumor suppressor genetumor suppressor gene ）） As a transcription factor, p53 regulates downstream genes impAs a transcription factor, p53 regulates downstream genes important in cell cycle arrest, DNA repair, and apoptosis. After DNA dortant in cell cycle arrest, DNA repair, and apoptosis. After DNA damage, p53 holds the cell at a checkpoint until the damage is repamage, p53 holds the cell at a checkpoint until the damage is repaired. If the damage is irreversible, apoptosis is triggered.aired. If the damage is irreversible, apoptosis is triggered.

Table . Human diseases associated with disordered apoptosis

Decreased Apoptosis Increased Apoptosis

Epithelial Tissue

Carcinogenesis Macrophages

Bacillary dysentery

Blood Vessels Intimal hyperplasia Myocardium Peri-infarct border zones

Lymphocytes Autoimmune disorders

Lymphocytes lymphocytes depletion in HIV injections and sepsis

Haemopoeitic systems

Leukemia, lymphoma

CNS Neurodegenerative diseases like Alzheimer’s and Parkinson’s disease

■■ bcl-2 overexpressionbcl-2 overexpression

In follicular lymphoma, a chromosomal translocation commonly occurs between the In follicular lymphoma, a chromosomal translocation commonly occurs between the

fourteenth and the eighteenth chromosomes-t(14;18)-which places the Bcl-2 gene nefourteenth and the eighteenth chromosomes-t(14;18)-which places the Bcl-2 gene ne

xt to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading xt to the immunoglobulin heavy chain locus. This fusion gene is deregulated, leading

to the transcription of excessively high levels of bcl-2. This decreases the propensity to the transcription of excessively high levels of bcl-2. This decreases the propensity

of these cells for undergoing apoptosis.of these cells for undergoing apoptosis.

（（ also observed in breast cancer, lung cancer, malanoma, prostate cancealso observed in breast cancer, lung cancer, malanoma, prostate cance

rr ））■■ pp53 deletion or mutation53 deletion or mutation

Abnormal of P53 in stability, localization or activationAbnormal of P53 in stability, localization or activation

pp53 expression or function defect apoptosis rate↓ tumorgenesis 53 expression or function defect apoptosis rate↓ tumorgenesis

（ （ abnormal P53 observed in at least 50% malignant cancerabnormal P53 observed in at least 50% malignant cancer ））

Apoptosis inhibitionApoptosis inhibition

1. Tumor1. Tumor

■■fusion proteinfusion protein

Chronic myeloid leukemiaChronic myeloid leukemia （（ CMLCML ） ） t (9t (9 ；； 22)( Ph chromoso22)( Ph chromoso

me)me)

Bcr-abl fusion geneBcr-abl fusion gene

NF-NF-B activationB activation 、、 inhibit apoptosis↓ p210inhibit apoptosis↓ p210 Bcr-abl Bcr-abl fusion protein fusion protein

CML cells proliferation leukemia CML cells proliferation leukemia

■■virus oncogenevirus oncogene

HBV encoded HBHBV encoded HBX X is inhibitor for Caspase-3, and is associated with livis inhibitor for Caspase-3, and is associated with liv

er cancer.er cancer.

22 ．． Autoimmune diseasesAutoimmune diseases

A common feature of autoimmune diseases is the breakdown of tA common feature of autoimmune diseases is the breakdown of tolerance of self antigens, a consequence of which is the productiolerance of self antigens, a consequence of which is the production of autoantibodies reactive with multiple self proteins. Defect on of autoantibodies reactive with multiple self proteins. Defect in apoptosis can cause autoimmunity by allowing the survival of in apoptosis can cause autoimmunity by allowing the survival of autoreactive T and B cells. autoreactive T and B cells.

Apoptosis excessApoptosis excess

1. 1. Ischemia reperfusion injuryIschemia reperfusion injury

■■characterscharacters

▲early phase apoptosisearly phase apoptosis ，， late phase necrosis.late phase necrosis.

▲in the centre of infarct necrosisin the centre of infarct necrosis ，， in the peri-infarct zone apoin the peri-infarct zone apoptosisptosis ；；

▲mild mild ischemiaischemia apoptosis apoptosis ，， severe severe ischemia necrosisischemia necrosis ；；

■■mechanismmechanism

▲oxidation oxidation ▲FasR FasR ▲p53p53 activation activation

Deregulated cell differentiation and Deregulated cell differentiation and Disease Disease

►►ConceptConcept

Cell differentiation is a process in which a generic cell develoCell differentiation is a process in which a generic cell develops into different kinds cells with the specialized morphology, metaps into different kinds cells with the specialized morphology, metabolism and physiological functions in response to specific triggers bolism and physiological functions in response to specific triggers from the body or the cell itself.from the body or the cell itself.

Cell differentiation is tightly regulated by a series of regulatory Cell differentiation is tightly regulated by a series of regulatory

proteins.proteins.

Ey gene in the Ey gene in the morphogenesis of eyesmorphogenesis of eyes

Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined Factors

Cell 2007,131,861-872 （ Oct3/4, Sox2, Klf4, c-Myc ）

Determination and differentiationDetermination and differentiation

The The determinationdetermination of different cell types (cell fates) involves of different cell types (cell fates) involves progressive restrictions in their developmental potentials. Wheprogressive restrictions in their developmental potentials. When a cell “chooses” a particular fate, it is said to be determined, n a cell “chooses” a particular fate, it is said to be determined, although it still "looks" just like its undetermined neighbors. Dalthough it still "looks" just like its undetermined neighbors. Determination implies a stable change - the fate of determined cetermination implies a stable change - the fate of determined cells does not change.ells does not change. Differentiation follows determination.

In some cases, determination results from the asymmetric segregation of cellular determinants. However, in most cases, determination is the result of inductive signaling between cells.

2. Regulation on transcription and post- transcription level2. Regulation on transcription and post- transcription levelss ））

■■transcription leveltranscription level

■■post-transcription levelpost-transcription level

The regulation of cell differentiationThe regulation of cell differentiation

1. Regulation on the genomic level1. Regulation on the genomic level ））

■■ House-keeping genesHouse-keeping genes

House-keeping genes generally encode proteins that House-keeping genes generally encode proteins that participate in basic or universal cellular functions essential for participate in basic or universal cellular functions essential for maintaining cell survival.maintaining cell survival.

■ ■tissue specific genetissue specific gene

3. tranlational and post-translational level3. tranlational and post-translational level

4. Extracellular factors that control differentiation4. Extracellular factors that control differentiation

Hem

atopoiesis

acute promyelocytic leukemia

“Acute promyelocytic leukemia (AML M3) is now the

most frequently curable acute leukaemia in adults if

promptly diagnosed and adequately treated.”Parmar S, Tallman MS. , 2003

1988: Breakthrough in treatment from China

1990: Multiple groups identify RAR as t(15; 17) breakpoint

How does ATRA induce remission?

How does PML-RAR induce APL?

Drug Gene

Morbid obesityMorbid obesity

Excess pre-adipocyte differentiate into adipocyte.Excess pre-adipocyte differentiate into adipocyte.

Pulmonary fibrosisPulmonary fibrosis

Pulmonary vascular lesionsPulmonary vascular lesions brinase↑↑↑brinase↑↑↑

myofibroblast collagenoblast collagen depositionmyofibroblast collagenoblast collagen deposition

hypoxhypox

ia gas diffusion disorder alveolar membrane thickeningia gas diffusion disorder alveolar membrane thickening