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Molecular Biology of Cancer

Molecular Biology of Cancer. Yuki Juan NTUST Jun 9, 2003. Outline. The cell cycle and its control What is the molecular nature of cancer How do oncogenes cause cancer What are the roles of tumour suppressor genes. Terms. Telomeres Telomerase Benign tumor Metastasis Leukaemias.

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Molecular Biology of Cancer

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  1. Molecular Biology of Cancer Yuki Juan NTUST Jun 9, 2003

  2. Outline • The cell cycle and its control • What is the molecular nature of cancer • How do oncogenes cause cancer • What are the roles of tumour suppressor genes

  3. Terms • Telomeres • Telomerase • Benign tumor • Metastasis • Leukaemias

  4. Growth Characterisitics of Normal and Cancerous Animals Cells In Culture

  5. Outline • The cell cycle and its control • What is the molecular nature of cancer • How do oncogenes cause cancer • What are the roles of tumour suppressor genes

  6. Cell Cycle Check Points

  7. Control Mechanism

  8. Outline • The cell cycle and its control • What is the molecular nature of cancer • How do oncogenes cause cancer • What are the roles of tumour suppressor genes

  9. Terms • Carcinogenic • Phorbol ester and diacylglycerol (DAG)

  10. What Types of Genetic Changes Are Involved In Generation Of The Cancerous State • Oncogenes • Tumor suppressor genes • Retinoblastoma genes • p53 genes • DNA repair genes

  11. How Are Oncogenes Acquired • Thay may be introduced by viral infection • Normal genes involved in control may mutate and become oncogenic • Oncogen and protooncogene

  12. Outline • The cell cycle and its control • What is the molecular nature of cancer • How do oncogenes cause cancer • What are the roles of tumour suppressor genes

  13. Oncogenicity May Include One or More of the Following • Signal transduction pathways leading to formation of active transcription factors may be inappropriately activated. • There may excessive amounts of particular transcription factors. • There may be abnormal transcription factors which are inappropriately active.

  14. Oncogen Products As Components of Signalling Pathways Normal receptor-not activated Normal receptor-activated Permanently active truncated EGF receptor Normal receptor-pathway component permanently active

  15. Outline • The cell cycle and its control • What is the molecular nature of cancer • How do oncogenes cause cancer • What are the roles of tumour suppressor genes

  16. Tumour Suppressor Genes • P53 genes • P53 protein: a transcription factor known to have several roles in cellular control • P53  p21  inactives the G1-specific Cdk activity • Apoptosis • Retinoblastoma genes • Retinoblastoma protein blocks the cycle at the G1 checkpoint

  17. My Study Yuki Juan

  18. Proteomics and Bioinformatics on Biomedical Sciences Hsueh-Fen Juan (阮雪芬) Nov 8, 2002

  19. Outline • Introduction • Identification of acute phase proteins in nude mice inoculated with different cancer cells • Bioinformatics • Peptide Mass Integrator (PMI) • Biomic study of human myeloid leukemia cell differentiated to macrophage • Bioinformatics • Bulk Gene Search System (BGSS) • Pathway Database Construction (BioMiner) • Conclusion • Outlook

  20. Outline • Introduction • Identification of acute phase proteins in nude mice inoculated with different cancer cells • Bioinformatics • Peptide Mass Integrator (PMI) • Biomic study of human myeloid leukemia cell differentiated to macrophage • Bioinformatics • Bulk Gene Search System (BGSS) • Pathway Database Construction (BioMiner) • Conclusion • Outlook

  21. Biochemical Context of Genomics and Proteomics Genome “Genomics” DNA mRNA Proteome “Proteomics” Proteins Cell functions

  22. The Information Stored in Genes Is Expressed by a Multistage Process Eur J Nucl Med 2002, 29, 115-32

  23. Two-dimensional Gel Approach Nature 2000, 405, 837-846

  24. Standard Proteome Analysis by 2DE-MS Mass Fingerprint Searching in http://www.expasych/tools/peptident.html Current Opinion in Chemical Biology 2000, 4:489–494

  25. Proteomics Applied to Drug-discovery

  26. Outline • Introduction • Identification of acute phase proteins in nude mice inoculated with different cancer cells • Bioinformatics • Peptide Mass Integrator (PMI) • Biomic study of human myeloid leukemia cell differentiated to macrophage • Bioinformatics • Bulk Gene Search System (BGSS) • Pathway Database Construction (BioMiner) • Conclusion • Outlook

  27. Our Study Serum from cancer nude mice Proteomics Tumor markers

  28. Cancer cells PBS Treatment Control Nude mice Serum Protein ID by MS/MS

  29. Control CCM1 pH 3 pH 3 10 10 10 11 97.0 97.0 97.0 66.0 66.0 66.0 12 C2 C3 45.0 45.0 45.0 3 C4 1 2 C1 4 30.0 30.0 30.0 6 7 5 C8 8 20.1 20.1 20.1 C5 13 15 C6 C7 14.4 14.4 14 9 14.4 GBM HONE 97.0 97.0 97.0 G1 G2 66.0 66.0 66.0 G3 G4 45.0 45.0 45.0 G5 30.0 30.0 30.0 20.1 20.1 20.1 G6 14.4 14.4 14.4 H2 H1 J5 SCM1 S11 S6 S5 J2 J1 S1 S3 S8 S4 S2 J3 J4 J5 S12 S13 S7 S9 S10

  30. Peptide Mass Fingerprinting http://us.expasy.org/tools/peptident.html

  31. Integrated Protein Identification Tools

  32. MALDI Peptide Map and Identification of a Protein

  33. Outline • Introduction • Identification of acute phase proteins in nude mice inoculated with different cancer cells • Bioinformatics • Peptide Mass Integrator (PMI) • Biomic study of human myeloid leukemia cell differentiated to macrophage • Bioinformatics • Bulk Gene Search System (BGSS) • Pathway Database Construction (BioMiner) • Conclusion • Outlook

  34. Create Summary Report Using NCBI nr database to perform query Get pI value of the first data Get pI value of the second data Get pI value of the third data Create summary report of NCBI nr query

  35. PMIhttp://www.taai.org.tw/MassData/ Progress Rate Query Result

  36. PMIQuery Result

  37. Protein Identification a. MALDI: LC/MS/MS: The LC/MS/MS total score for a match contains contributions from the peptide mass matches, ions scores (from queries with MS/MS data), and amino acid sequence or composition qualifiers (sequence queries). Score is -10Log(P), where P is the probability that the observed match is a random event. b. Molecular weight observed on 2D gel / Theoretical molecular weight

  38. Acute Phase Proteins in Nude Mice Inoculated with Different Cancer Cells

  39. Identification of Serum Amyloid Ain Serum of Nude Mice Inoculated with Cell Line of Stomach Adenocarcinoma SC-M1 MW 97 66 45 30 20.1 S10 S9 14.4 5 6

  40. Quantification of S9 and S10 S9( 2 fold) S10 (+) Control Control (-) Analysis by Porgenesis

  41. Nanoelectrospray Mass Spectrometry S9: Serum Amyloid A-2 S10: Serum Amyloid A-1

  42. 02-0511 97000 66000 45000 30000 20100 14400 5 6 Haptoglobin ( α form ) in Serum of Nude Mice Inoculated with Cell Line of Stomach Adenocarcinoma SC-M1 Control S7

  43. SCM1-1(胃癌) 02-0511 97000 66000 45000 30000 20100 14400 b 129.07 315.15 414.21 985.47 528.26 629.3 728.37 799.41 856.43 5 6 Gln Trp Val Asn Thr Val Ala Gly Glu Lys y 1003.5 817.44 718.37 604.33 503.28 404.21 333.18 276.16 147.11 Haptoglobin (βform )

  44. Acute Phase Response • In mice, Haptoglobin and hemopexin • The early stages of inflammatory responses are characterized by the rapid synthesis of a heterogenous group of plasma proteins known as acute phase reactants (proteins). • In man, C-reactive protein (CRP) or serum amyloid A component (SAA) 1000-fold Clin Exp Immunol 1986, 66(2):331-9 Scand J Immunol 1984, 19: 193-198

  45. Outline • Introduction • Identification of acute phase proteins in nude mice inoculated with different cancer cells • Bioinformatics • Peptide Mass Integrator (PMI) • Biomic study of human myeloid leukemia cell differentiated to macrophage • Bioinformatics • Bulk Gene Search System (BGSS) • Pathway Database Construction (BioMiner) • Conclusion • Outlook

  46. Our Study Human myeloid leukemia cells Genomic Study TPA Proteomics Bioinformatics Macrophages

  47. Macrophage

  48. The Structure of TPA 12-O-tetradecanoyl-phorbol-13-acetate

  49. HL-60 Leukemia Cell Differentiate to Macrophage HL-60 Cell Macrophage Myeloblast Proteins ?

  50. HL-60 Leukemia Cell Differentiate to Macrophage Control Treated with TPA

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