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 persistantMAPK 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

G1 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 mostcommon target for geneticinsults leading to cancer

DNA damage stabilizes p53and 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 (oncogeneactivation, 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 CancerShachaf 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.

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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 CancerShachaf 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.