생명현상의 Overview : 생명현상의 분자기전
Information
생체정보 : hormone, cytokines, neurotransmitter→세포→유전
O2/영양분 cytokines neurotransmitters Hormones
1st messenger
당질
(당뇨병)
지질→저장
(비만, 동맥경화)
-omics
2nd messenger
°Physiome
Southern blot
 Northern blot
Genome=gene+chromosome
-sequencing
-SNP chip
 Western blot
AAA
Vt B
TCA
Protein
(생리기능)
Transcriptome: DNA chip, mRNA seq
mRNA
Vt C, E
NADH
themogenin
ATP
Cell homeostasis
Proteome
-2D/Maldi-Top Mass
a.a
열
단백질
Maintenance
E小
Hormesis
Cell proliferation (replication)
E多
Seven processes that affect the
steady-state concentration of a protein
* 호르몬과 표적기관
calcitonin : C세포에서 분비 Ca저하
Physiological information cascade
GHRH(GH)
GnRH(CH,FSH)
TRH(TSH)
CRH(ACTH)
T3/T4
glucocorticoid
aldosterone
GHIH
PRIH



뼈에서 유리
신장 재흡수
* Cellular signal transduction
Cortisol
Insulin
GFs
Glucagon
Epinephrine
Tyr kinase
Akt
SREBP
ChREBP
Tf 인산화
<세포의 자극에 의한 유전자 발현 조절>
Intracellular Receptor
 Steroid hormone
 Carrier에 의해 표적세포까지 이동 carrier 해리 단순수송 intracellular
receptor 핵공 통과 DNA 결합 전사조절
Protein Kinase A (cAMP)
CREB: CRE binding protein
Receptor Tyrosine Kinase
 Receptor tyrosine kinases (TKs or RTKs) phosphorylate specific tyrosines
on a small set of intracellular signaling proteins.
Insulin
EGF, VEGF, MCSF
PDGF, HGF, IGF-1
FGF, NGF
Insulin
 ligand binding에 의한 dimerization  autophosphorylation
 신호반응의 종결
Protein tyrosine phosphatase에 의한 탈인산화 반응
Receptor의 endocytosis로 lysosome 에서 분해
IL-1
IL-1R
TNFα
ㅑ
Insulin
ㅜ
TNFR
IR
Shc
TRAF6 TRAF2 TRADD
IRAK
IRS-1 IRS-2
Cell proliferation
NF-κB
Inflammation
COX-2
INF
Fasting
Glucagon
SIRT1
(NAD)
AMPK
(AMP)
PI3K
MAPKs
NIK
IKK
Epinephrine
Akt
Cholesterol
synthesis
HMG-CoA
reductase
Squalene
synthase
SREBP2
Cyclin D/E
mTOR
Cell
cycle
GSK3
GS
G
protein
PKA
Glut4
translocation
SREBP1
CREB
ChREBP
4E-BP
Glucose
uptake
4E
Autophagy
(protein degradation)
Glycogen
synthesis
cAMP
ATP
PGC-1α
FA FAS, ACC
synthesis
Glycolysis
FOXO
HNF-4
FA synthesis
Translation
(protein synthesis)
Gluconeogenesis
PEPCK G6Pase
Biosignaling in inflammation and metabolism
Extensive Single DNA
Bulky DNA lesion , DNA Excision Repair
Single strand breaks
IR Radiation
DNA Double strand breaking
Ku
ATM
DNA-PK
Activity ▲
Translocation
ATR
P
P
p53
P
Chk2
Chk1
P
DNA 절단
말단 결합
BRCA1
Translocation
p21
Recombinational
Repair
cdc25
Cdc2
(CDK1)
p21
CDK2
M-Phase
CDK2
Cyclin E
G1-Phase
Cyclin B
G2-Phase
Cyclin A
S-Phase
P
RB
RB
DNA damage signaling and cell cycle
E2F
E2F
G1-S phase
Cell cycle progress
Small RNA
a) small nuclear
RNA(snRNA): splicing,
100-200b
b) small nuleolar
RNA(snoRNA): rRNA
modification, cleavage,
60-300b
c)microRNA(miRNA):RNA
번역억제, 절단, gene
regulation, 22b, genome
1%, by RNase III
d) si RNA: small interfering RNA, RNA절단
RNA interference(RNAi): siRNA, shRNA
: RNase III의 일종
:RNA-induced silencing
Complex(RISC)
cf) RNA interference(RNAi)
siRNA, shRNA
FIGURE 26-28 Synthesis and processing of miRNAs.
RNAi (RNA interference)
『21-25nt의 small size RNA에 의해 상보적인 염기서열을 갖는 mRNA가 선택적으로 분해되
거나 translation이 억제되는 현상』
Types of RNAi
miRNA : micro RNA
siRNA : short interfering RNA or small interfering RNA
shRNA : short hairpin RNA or small hairpin RNA
• Which type of si-/shRNA should be used?
Time –speed
Stablility
How long
Price
-
: siRNA > shRNA
: siRNA < shRNA - vector
: siRNA < shRNA
: siRNA > shRNA
siRNA
shRNA
RNAi Overview
Fig 23.24. Cartoon of final initiation complex
GR
Glucagon, epinephrine
PKA
Insulin
Tyr kinase
CREB
Akt
SREBP
Fig 23.18. Examples of transcription factor activation
eIF-4F:
eIF-4E, 4G,4A(PAB과
Cap에 결합)
eIF-4F
eIF-4E 번역조절인자
mTOR
eIF-4F의 eIF-4E소단위체가
4E-BP와 결합하면 번역
저해
신장인자가 4E-BP에서
인산화되면, 4E-BP와 elF4E와 결합방해,
단백질합성촉진
translation
<4> Receptor-Mediated
Endocytosis :coated pits, clathrin,
caveolin
<5> Protein Degradation
1)Lysosomal: major
a)endocytosis b)autophagy
2)Cytosolic
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
IL-1
IL-1R
TNFα
ㅑ
Insulin
ㅜ
TNFR
IR
Shc
TRAF6 TRAF2 TRADD
IRAK
IRS-1 IRS-2
Cell proliferation
NF-κB
Inflammation
COX-2
INF
Fasting
Glucagon
SIRT1
(NAD)
AMPK
(AMP)
PI3K
MAPKs
NIK
IKK
Epinephrine
Akt
Cholesterol
synthesis
HMG-CoA
reductase
Squalene
synthase
SREBP2
Cyclin D/E
mTOR
Cell
cycle
GSK3
GS
G
protein
PKA
Glut4
translocation
SREBP1
CREB
ChREBP
4E-BP
Glucose
uptake
4E
Autophagy
(protein degradation)
Glycogen
synthesis
cAMP
ATP
PGC-1α
FA FAS, ACC
synthesis
Glycolysis
FOXO
HNF-4
FA synthesis
Translation
(protein synthesis)
Gluconeogenesis
PEPCK G6Pase
Biosignaling in inflammation and metabolism
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
Ames test
∙∙∙”발암가능성 물질
(carcinogen)” 선별하는
값싸고 빠른 방법
ex)”Salmonella
typhimurium”
→histidine 생합성경로
의 효소를
불활성화
시키는 돌연변이
FIGURE 25-21 Ames test for carcinogens, based on their mutagenicity.
암예방, 항암
Gene therapy
RNAi
-GFs signaling: Tyr kinase
-Apoptosis
-Differentiation
-Epigenetic regulation
Anti-angiogenesis
Immunotherapy