OncologicalPharmacologyIV生长调控,癌基因与抑癌基因教程分析.ppt

Growth regulation, oncogene and tumor suppressor genes 生长调控，癌基因与抑癌基因 2011-4-7 I. Oncogene-Lessons from the Virus From RSV to Src: A Chicken Story Tumor transferred by acellular supernatant(1911) Dr. Peyton Rous. (Rockefeller Univ. Archives) The Discovery of Rous Sarcoma Virus(RSV) Before that, solid tumors were thought to only induced intrinsically! The Rous Sarcoma Virus(RSV) /jkimball.ma.ultranet/BiologyPages/R/RSV.html Replication-defective vs transformation-defective variants of RSV Oncogene 23, 7910–7917 The Nobel Prize in Physiology or Medicine 1989 Photos: Copyright ? The Nobel Foundation J. Michael Bishop Harold E. Varmus The discovery of the cellular origin of retroviral oncogenes, 1976 Nat. Rev. Mol. Cell Bio. 2, 467-475 BBA Rev. on Cancer. 1602, 2, 114-130 V-Src vs c-Src Signaling by c-Src Nat. Rev. Mol. Cell Bio. 2, 467-475 The History of Src Nat. Rev. Mol. Cell Bio. 2, 467-475 Proto-Oncogene-Lessons from the Virus v-Src (from RSV) vs c-Src v-Myc (from CMV) vs c-Myc v-Ras (from H- and K- sarcoma virus) vs c-Ras v-ErbB (from Avian Erthroblastosis Leukemia Virus) vs c-ErbB (EGF) …… Proto-Oncogenes Growth Factors (PDGF, VEGF) Growth Factor Receptors (PDGFR, VEGFR) Intracellular Signaling Transducers (Ras, Src) Transcription Factors (Myc, Jun, Fos) Proto-Oncogene Activation Over-expression Abnormal activation Loss of suppression More cases: c-ErbB2 in Breast Cancer More cases: c-ErbB3 in Prostate Cancer Cheng C et al. Mol Cancer Res 2007;5:675-684 More cases: p-Src and c-ErbB-R(EGFR) in NSCLC Leung E L et al. Mol Cancer Res 2009;7:923-932 The ErbB(EGF) Family Members The ErbB(EGF) Signaling Pathway EGF Signaling Growth factor binding Receptor dimerizing Auto-phosphorylation Translocation of specific proteins to the membrane (Grb2, SOS) RAS activation Raf activation MAP kinase cascade (ERK, JNK, P38) Regulation of Transcription factors The ErbB(EGF) Signaling Pathway The ErbB(EGF) Trans-activation by GPCR New and Wong Journal of Molecular Signaling 2