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 Ras and Raf oncogenes are constitutively active persistant MAPK signaling unregulated gene transcription The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

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 Degradation of p27 Phosphorylation of inhibitory Rb protein Increased activity of E2F Cells continue through cell cycle G1G1 S Increased activity of Cyclin/CDK complexes MYC and the Cell Cycle (CDK inhibitory protein)

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 Rb prevents E2F transcription factor from transcribing genes inappropriately Loss of Rb allows for unregulated gene transcription The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

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.

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, %Survival Time (weeks) +Dox (MYC off) -Dox (MYC on) +Dox (MYC off) -Dox (MYC on) -Dox +Dox (MYC on) (MYC off)

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.