MolBio_Sp04_pres_20

Proto-oncogene to Oncogene


Retrovirus induced cancers are rare in humans Most cancers involve mutation in cellular proto-oncogene to produce an oncogene Three ways to produce oncogene



Point mutation to alter regulation of gene or gene product Localized amplification of gene to cause overexpression of gene product nslocation of gene into new location leading to loss of regulation
Amplification of Oncogenes



Point mutations and translocations convert proto-oncogenes to oncogenes Conversion can also result from amplification Myc oncogene is amplified in neuroblastoma ErbB oncogene is amplified in many breast tumors
Molecular Basis of Cancer




Transformation of a normal cell into a malignant cancer cell requires DNA damage The DNA damage events alter genes involved in controlling cell growth Much is known about specific molecular events that lead to cancer Research dates to 1911 when Peyton Rous discovered the first oncogenic virus

Won’t respond to GAP


MAP kinase pathway is always “on” Cell cycle is always running
Several Proto-Oncogenes in MAP Kinase Pathway


Class II, growth factor receptor is ErbB Normally binds epidermal growth factor (EGF) to activate the cell cycle Deletion causes loss of growth factor dependence





Src is a protein-tyrosine kinase (class III, intracellular transducer oncogene) Phosphorylates proteins that activate the cell cycle So, when RSV genome inserts into host chromosome, src gene is expressed Src kinase activates cell cycle Cell loses control of division
Rous Sarcoma Virus (RSV)




First demonstration of a cause for cancer Infect chickens with RSV Sarcoma develops within 2 weeks RSV is a retrovirus Nobel for Rous in 1966
Several Class III Oncogenes


Intracellular transducers in MAP kinase pathway are all oncogenes Ras, raf, mek, erk, elk Mutations in any of these genes can cause loss of cell cycle regulation
MAP Kinase Pathway 15.26



Ras is a signaling molecule (kinase transducer) in the MAP kinase pathway Long signal transduction pathway that ends in production of Fos Fos is a transcription factor that activates genes involved in the G1 to S transition
Oncogenes are also in Genome


Key experimental finding: Genes that cause cancer (oncogenes) are also found in normal genomes They are normal cellular genes They have normal cellular functions In the cell they are called proto-oncogenes There are several ways to convert a protooncogene into an oncogene
Retrovirus Genome 15.17

Only 3 genes, gag pol and env
Oncogenic Retrovirus Genome





Oncogenic retroviruses like RSV have an extra gene Not required for viral multiplication Causes transformation to cancer cell 15.19 Called oncogene Activates cell cycle (proliferation) Over 40 different viral oncogenes see table 15.3 Src in RSV
For Example, Src




Src gene is in cellular genome When expressed, src gene product (kinase) activates cell cycle Expression and activity of src is regulated Cellular src protein is kept inactive by a key phosphorylation Viral src does not have phosphorylation target region Viral version is not regulated at either expression or activity
Ras is a G-Protein


GDP bound form is inactive Guanine nucleotide exchange factor (GEF) stimulates exchange to GTP form GTPase activating protein (GAP) stimulates GTP hydrolysis

Why so long?
Retrovirus Replication Cycle


Retroviruses convert an RNA genome into double-stranded DNA The DNA copy then integrates into the host chromosome Genome has only 3 genes
Ras 15.23




Large number of human cancers have mutated ras gene Normal product is an intracellular transducer Some tumor initiating mutations in ras can be as simple as a single nucleotide change Mutated gene product cannot be regulated Constant activation of growth factor pathway
Ras-GTP Activates Raf

Begins phosphorylation cascade Cascade ends in the nucleus with new gene expression
Chemical Carcinogens Mutate Ras


Several chemical carcinogens have been shown to induce point mutations in ras Converts proto-oncogene to oncogene Mutant protein does not hydrolyze GTP
Myc Oncogene 15-24