Transcript Cancer
March 5, 2009 Lecture Outline • Oncogenes • Tumor Suppressor Genes • Multiple Hit Hypothesis • Oncogene Addiction Hypothesis Oncogenes • Oncogene: “onco” (cancer) gene • 1989 Nobel Prize in Medicine or Physiology: The Discovery of the Cellular Origin of Retroviral Oncogenes – J. Michael Bishop (UCSF) – Harold Varmus (UCSF) Oncogenes Cont’d • Proto-oncogenes: normal cellular genes usually involved in cell growth and/or cell division • Oncogenes: a proto-oncogene that has been activated by mutation or overexpression. Results in a dominant gain of function phenotype – Growth Factors, Growth Factor Receptors, G-proteins, Kinases, Gene Regulatory Proteins Oncogene Activation Molecular Biology of the Cell. Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York and London: Garland Science; c2002 Ras/Raf Oncogenic Signaling The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000 Ras and Raf oncogenes are constitutively active persistant MAPK signaling unregulated gene transcription MYC Oncogene • Normal nondividing cells – Myc levels are low but responsive to growth signals from the cellular environment • Dividing cells – Myc levels constantly maintained at an intermediate level throughout cell cycle • Oncogenic MYC – Point mutation prevents MYC degradation allows for accumulation of high levels of MYC – Increased transcriptional activity MYC and the Cell Cycle MYC Degradation of p27 (CDK inhibitory protein) Increased activity of Cyclin/CDK complexes Phosphorylation of inhibitory Rb protein Increased activity of E2F G1 S Cells continue through cell cycle Common Human Oncogenes The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000 Tumor Suppressor Genes • Genes that are normally involved in the inhibition of cell growth and proliferation. • Two Hit Hypothesis: Tumor suppressor genes act in a recessive manner – Need loss of both alleles to progress towards cancer Molecular Biology of the Cell. Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. New York and London: Garland Science; c2002 Common Human Tumor Suppressor Genes The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000 Retinoblastoma (Rb) Tumor Suppressor Gene The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000 Rb prevents E2F transcription factor from transcribing genes inappropriately Loss of Rb allows for unregulated gene transcription p53 Tumor Suppressor Gene p53 is the single most common target for genetic insults leading to cancer DNA damage stabilizes p53 and allows for p53 accumulation p53 induces p21 (CDKN1A, CIP1, WAF1) to cause cell cycle arrest Robbins & Cotran Basic Pathology 7th ed Multiple Hit Hypothesis Cancer is due to an accumulation of genetic insults (oncogene activation, loss of tumor suppressor genes) Oncogene Addiction Hypothesis • Cells become addicted to persistent oncogene activity for proliferation – Become unresponsive to any other mitogenic (growth) stimuli • Turn off MYC and cells can respond to other stimuli – Tumor cells begin to become more normal MYC Oncogene Addiction in Hepatocellular Carcinoma Felsher, et al. QuickTime™ and a TIFF (Uncompressed) decompressor are needed to see this picture. +Dox (MYC off) -Dox (MYC on) -Dox +Dox (MYC on) (MYC off) %Survival +Dox (MYC off) QuickTime™ and a TIFF (Uncompressed) decompres sor are needed to see this picture. -Dox (MYC on) Time (weeks) MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular Cancer Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandi S, Bachman MH, Borowsky AD, Ruebner B, Cardiff RD, Yang Q, Bishop JM, Contag CH, Felsher DW. Nature. Vol431, 2004. MYC Inactivation Uncovers Pluripotent Differentiation and Tumor Dormancy in Hepatocellular Cancer Shachaf CM, Kopelman AM, Arvanitis C, Karlsson A, Beer S, Mandi S, Bachman MH, Borowsky AD, Ruebner B, Cardiff RD, Yang Q, Bishop JM, Contag CH, Felsher DW. Nature. Vol431, 2004.