생명현상의 Overview : 생명현상의 분자기전

1. 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 mRNA AAA Vt B • Genome=gene+chromosome -sequencing -SNP chip Transcriptome: DNA chip, mRNA seq Proteome -2D/Maldi-Top Mass  Western blot TCA Vt C, E Protein (생리기능) NADH themogenin ATP Cell homeostasis a.a 열 단백질 Maintenance Cell proliferation (replication) E小 E多 Hormesis

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

3. * 호르몬과 표적기관 calcitonin : C세포에서 분비 Ca저하 Physiological information cascade GHRH(GH) GnRH(CH,FSH) TRH(TSH) CRH(ACTH) GHIH PRIH    T3/T4 뼈에서 유리 신장 재흡수 glucocorticoid aldosterone

4. * Cellular signal transduction Insulin GFs Glucagon Epinephrine Cortisol Tyr kinase Akt SREBP ChREBP Tf 인산화 <세포의 자극에 의한 유전자 발현 조절>

5. Intracellular Receptor • Steroid hormone • Carrier에 의해 표적세포까지 이동 carrier 해리 단순수송 intracellular receptor 핵공 통과 DNA 결합 전사조절

6. Protein Kinase A (cAMP) CREB: CRE binding protein

7. Receptor Tyrosine Kinase • Receptor tyrosine kinases (TKs or RTKs) phosphorylate specific tyrosines on a small set of intracellular signaling proteins. Insulin EGF, VEGF, M-CSF 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

8. Insulin ㅑㅜ Epinephrine IR Fasting Glucagon TNFα IL-1 TNFR SIRT1 (NAD) IL-1R Shc AMPK (AMP) TRAF2 IRS-1 TRADD IRS-2 TRAF6 G protein IRAK MAPKs PI3K Cholesterol synthesis HMG-CoA reductase Squalene synthase NIK SREBP2 ATP cAMP Cell proliferation Akt IKK Cyclin D/E PKA NF-κB GSK3 SREBP1 mTOR Glut4 translocation Cell cycle CREB GS Inflammation COX-2 INF ChREBP 4E-BP PGC-1α FA synthesis FAS, ACC Glucose uptake Glycogensynthesis 4E FOXO HNF-4 Glycolysis Autophagy (protein degradation) FA synthesis Translation (protein synthesis) Gluconeogenesis PEPCK G6Pase Biosignaling in inflammation and metabolism

9. Extensive Single DNA Bulky DNA lesion , DNA Excision Repair Single strand breaks IR Radiation DNA Double strand breaking Ku Activity ▲ Translocation ATM ATR DNA-PK P P P p53 Chk2 Chk1 P DNA 절단 말단 결합 BRCA1 Translocation cdc25 Recombinational Repair p21 Cdc2 (CDK1) Cyclin B G2-Phase M-Phase p21 CDK2 CDK2 Cyclin E Cyclin A G1-Phase S-Phase P RB E2F G1-S phase Cell cycle progress RB E2F DNA damage signaling and cell cycle

10. Small RNA a) small nuclear RNA(snRNA): splicing, 100-200bb) small nuleolar RNA(snoRNA): rRNA modification, cleavage, 60-300bc)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

11. : RNase III의 일종 :RNA-induced silencing Complex(RISC) cf) RNA interference(RNAi) siRNA, shRNA FIGURE 26-28 Synthesis and processing of miRNAs.

12. RNAi (RNA interference) 『21-25nt의 small size RNA에 의해 상보적인 염기서열을 갖는 mRNA가 선택적으로 분해되거나 translation이 억제되는 현상』

13. 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 : siRNA > shRNA Stablility : siRNA < shRNA - vector How long : siRNA < shRNA Price : siRNA > shRNA - siRNA shRNA

14. RNAi Overview

15. Fig 23.24. Cartoon of final initiation complex

18. GR Glucagon, epinephrine PKA CREB Tyr kinase Akt Insulin SREBP Fig 23.18. Examples of transcription factor activation

21. eIF-4F:eIF-4E, 4G,4A(PAB과 Cap에 결합) eIF-4F

22. eIF-4E 번역조절인자 eIF-4F의 eIF-4E소단위체가 4E-BP와 결합하면 번역 저해 신장인자가 4E-BP에서 인산화되면, 4E-BP와 elF-4E와 결합방해, 단백질합성촉진 mTOR translation

23. <4> Receptor-Mediated Endocytosis :coated pits, clathrin, caveolin <5> Protein Degradation 1)Lysosomal: major a)endocytosis b)autophagy 2)Cytosolic ubiquination/proteasome

24. What is Autophagy? • A process of cellular self-degradation of cytoplasmic components via the lysosomal pathway • Macroautophagy/Microautophagy/Chaperone-mediated autophagy (CMA) • Macroautophagy  mitophagy/micorpexophagyor macropexophay/reticulophagy piecemeal microautophagy of the nucleus/ribophagy

25. Proteasome FIGURE 27-48 Three-dimensional structure of the eukaryotic proteasome

26. Insulin ㅑㅜ Epinephrine IR Fasting Glucagon TNFα IL-1 TNFR SIRT1 (NAD) IL-1R Shc AMPK (AMP) TRAF2 IRS-1 TRADD IRS-2 TRAF6 G protein IRAK MAPKs PI3K Cholesterol synthesis HMG-CoA reductase Squalene synthase NIK SREBP2 ATP cAMP Cell proliferation Akt IKK Cyclin D/E PKA NF-κB GSK3 SREBP1 mTOR Glut4 translocation Cell cycle CREB GS Inflammation COX-2 INF ChREBP 4E-BP PGC-1α FA synthesis FAS, ACC Glucose uptake Glycogensynthesis 4E FOXO HNF-4 Glycolysis Autophagy (protein degradation) FA synthesis Translation (protein synthesis) Gluconeogenesis PEPCK G6Pase Biosignaling in inflammation and metabolism

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

28. Figure 23-31 Obesity caused by defective leptin production.

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

33. 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

34. Carcinogenesis

35. Ames test ∙∙∙”발암가능성 물질(carcinogen)”선별하는 값싸고 빠른 방법 ex)”Salmonella typhimurium” →histidine 생합성경로의 효소를 불활성화시키는 돌연변이 FIGURE 25-21 Ames test for carcinogens, based on their mutagenicity.

37. 암예방, 항암

38. Gene therapy RNAi -GFs signaling: Tyr kinase -Apoptosis -Differentiation -Epigenetic regulation Anti-angiogenesis Immunotherapy