Information

생체정보 : hormone, cytokines, neurotransmitter→ 세포→유전

O2/영양분 cytokines neurotransmitters Hormones 1st messenger

당질( 당뇨병 )

지질→저장( 비만 , 동맥경화 )

-omics

°Physiome

Genome=gene+chromosome-sequencing -SNP chip Transcriptome: DNA chip, mRNA seq

Proteome -2D/Maldi-Top Mass

Hormesis

Maintenance

E 小Cell proliferation (replication)

E 多

2nd messenger

Southern blot Northern blot

Western blot

단백질

열

Protein( 생리기능 )

Cell homeostasis

themogeninATP

Vt C, E

a.a

mRNA Vt BAAA

TCA

NADH

Seven processes that affect the steady-state concentration of a protein

* 호르몬과 표적기관 calcitonin : C 세포에서 분비 Ca 저하

GHIHPRIH

GHRH(GH)GnRH(CH,FSH)TRH(TSH)CRH(ACTH)

T3/T4

뼈에서 유리신장 재흡수glucocorticoid

aldosterone

Physiological information cascade

* Cellular signal transduction

< 세포의 자극에 의한 유전자 발현 조절 >

Tf 인산화

CortisolGlucagonEpinephrine

InsulinGFs

Tyr kinase

Akt

SREBPChREBP

Steroid hormone Carrier 에 의해 표적세포까지 이동 carrier 해리 단순수송 intracellular

receptor 핵공 통과 DNA 결합 전사조절

Intracellular Receptor

Protein Kinase A (cAMP)

CREB: CRE binding protein

Receptor tyrosine kinases (TKs or RTKs) phosphorylate specific tyrosines on a small set of intracellular signaling proteins.

ligand binding 에 의한 dimerization autophosphorylation   신호반응의 종결

Protein tyrosine phosphatase 에 의한 탈인산화 반응Receptor 의 endocytosis 로 lysosome 에서 분해

EGF, VEGF, M-CSF PDGF, HGF, IGF-1FGF, NGFInsulin

Receptor Tyrosine Kinase

Insulin

IRS-1IRS-2

PI3K

Akt

Shc

MAPKs

Cell proliferation

NIK

TNFα

TRADD

TNFR

TRAF2

IKK

NF-κB

Inflammation

COX-2INF

IL-1

IL-1R

TRAF6

IRAK

Cyclin D/E

Cell cycl

e

mTOR

4E-BP

GSK3

GS

Glycogensynthesis

ChREBP

Glucose uptake

Glut4 translocation

Glycolysis

FA synthesis

Glucagon

Epinephrine

SREBP1

FA synthes

is

FAS, ACC

SREBP2

Cholesterol

synthesisHMG-CoA reductaseSqualene synthase

Cholesterol

synthesisHMG-CoA reductaseSqualene synthase

Fasting

SIRT1 (NAD)AMPK

(AMP)G

protein

ATP cAMP

PKA

CREB

PGC-1α

FOXO HNF-4

Gluconeogenesis

PEPCK G6Pase

IR

ㅑㅜInsulin

Biosignaling in inflammation and metabolism

4E4E

Translation(protein synthesis)

Translation(protein synthesis)

Autophagy(protein degradation)

IR RadiationDNA Double strand breaking

Extensive Single DNABulky DNA lesion , DNA Excision RepairSingle strand breaks

ATM ATRActivity ▲

Translocation

p53

P

Chk2

P

Translocation

p21

p21

Cyclin E

Cyclin E

CDK2

CDK2

G1-Phase S-PhaseCyclin A

Cyclin A

CDK2

CDK2

Chk1

P

cdc25

Cyclin B

Cyclin B

Cdc2(CDK1

)

Cdc2(CDK1

)

G2-Phase M-Phase

RB E2FG1-S phaseCell cycle progress

RB E2F

P

BRCA1

P

RecombinationalRepair

Ku

DNA-PK

DNA 절단 말단 결합

DNA damage signaling and cell cycle

a) small nuclear RNA(snRNA): splicing,

100-200bb) small nuleolar

RNA(snoRNA): rRNA modification, cleavage,

60-300b

c)microRNA(miRNA):RNA 번역억제 , 절단 , gene

regulation, 22b, genome 1%, by RNase III

Small RNA

d) si RNA: small interfering RNA, RNA 절단 RNA interference(RNAi): siRNA, shRNA

: RNase III 의 일종

:RNA-induced silencingComplex(RISC)

FIGURE 26-28 Synthesis and processing of miRNAs.

cf) RNA interference(RNAi) siRNA, shRNA

RNAi (RNA interference)

『 21-25nt 의 small size RNA 에 의해 상보적인 염기서열을 갖는 mRNA 가 선택적으로 분해되거나 translation 이 억제되는 현상』

Types of RNAi

miRNA : micro RNA

siRNA : short interfering RNA or small interfering RNA

shRNA : short hairpin RNA or small hairpin RNA

siRNA

shRNA

Time –speed : siRNA > shRNAStablility : siRNA < shRNA - vectorHow long : siRNA < shRNAPrice : siRNA > shRNA -

• Which type of si-/shRNA should be used?

RNAi Overview

Fig 23.24. Cartoon of final initiation complex

Fig 23.18. Examples of transcription factor activation

Glucagon, epinephrine

InsulinTyr kinase

PKA CREB

GR

Akt

SREBP

eIF-4F:eIF-4E, 4G,4A(PAB 과 Cap 에 결합 )

eIF-4F

eIF-4E 번역조절인자

eIF-4F 의 eIF-4E소단위체가 4E-BP 와 결합하면 번역 저해

신장인자가 4E-BP 에서 인산화되면 , 4E-BP 와 elF-4E 와 결합방해 , 단백질합성촉진

mTOR

translation

<4> Receptor-Mediated Endocytosis :coated pits, clathrin, caveolin

<5> Protein Degradation

1)Lysosomal: major

a)endocytosis b)autophagy

2)Cytosolic

ubiquination/proteasome

What is Autophagy?

A process of cellular self-degradation of cytoplasmic components via the lysosomal pathway

Macroautophagy/Microautophagy/Chaperone-mediated autophagy (CMA)

Macroautophagy mitophagy/micorpexophagy or macropexophay/reticulophagy piecemeal microautophagy of the nucleus/ribophagy

Proteasome

FIGURE 27-48 Three-dimensional structure of the eukaryotic proteasome

IRS-1IRS-2

PI3K

Akt

Shc

MAPKs

Cell proliferation

NIK

TNFα

TRADD

TNFR

TRAF2

IKK

NF-κB

Inflammation

COX-2INF

IL-1

IL-1R

TRAF6

IRAK

Cyclin D/E

Cell cycl

e

mTOR

4E-BP

GSK3

GS

Glycogensynthesis

ChREBP

Glucose uptake

Glut4 translocation

Glycolysis

FA synthesis

Glucagon

Epinephrine

SREBP1

FA synthes

is

FAS, ACC

SREBP2

Cholesterol

synthesisHMG-CoA reductaseSqualene synthase

Cholesterol

synthesisHMG-CoA reductaseSqualene synthase

Fasting

SIRT1 (NAD)AMPK

(AMP)G

protein

ATP cAMP

PKA

CREB

PGC-1α

FOXO HNF-4

Gluconeogenesis

PEPCK G6Pase

IR

ㅑㅜInsulin

Biosignaling in inflammation and metabolism

4E4E

Translation(protein synthesis)

Translation(protein synthesis)

Autophagy(protein degradation)

Figure 23-30 Set-point model for maintaining constant mass.

Figure 23-31 Obesity caused by defective leptin production.

Figure 23-32 Hypothalamic regulation of food intake and energy expenditure.

Cancer

-Chemical/Radiation>>mutation>>transformation>>proliferation>>cancer-Virus>>oncogene>>> 발암촉진

*Oncogene 활성화 : mutation, translocation, deletion*Tumor suppressor gene(anti-oncogene):p53, Rb mutation>>hypermethylation*Cell cycle-p53, Rb

Carcinogenesis

FIGURE 25-21 Ames test for carcinogens, based on their mutagenicity.

Ames test

∙∙∙” 발암가능성 물질(carcinogen)” 선별하는 값싸고 빠른 방법

ex)”Salmonella typhimurium”

→histidine 생합성경로의 효소를 불활성화시키는 돌연변이

암예방 , 항암

RNAi

Gene therapy

Anti-angiogenesis

Immunotherapy

-GFs signaling: Tyr kinase-Apoptosis-Differentiation-Epigenetic regulation