ONCOGENES

• Cancer – disease in which cells grow abnormally, disorganized and unresponsive to normal growth restraints
• Oncogenes – genes that cause a cell to become cancerous; code for production of proteins involved in growth control
• Proto-oncogenes – genes that regulate normal cell proliferations, codes growth-controlling proteins, transformable to oncogenes

Classes of Growth Controlling Proteins

Class Description Example
polypeptide hormones (eg. EGF, IGF, TGF, CSF, PDGF), pure
Growth factors sis = platelet-derived GF = simian sarcoma virus (sv40)
signals, no metabolic purpose
Surface: fms (CSF-1), erb-B (EGF), neu (EGF-related),
Growth factor ros (insulin-like GF)
cell-surface or intracellular, sensitive to the signal
receptors Nuclear: erb-A (thyroid hormone
receptor-like)
Protein-tyrosine kinase – src, abl,
fps/fes
2nd messengers, cytoplasmic or plasma serine/threonine kinase – raf, mos
membrane proteins that transmit signals from ras-proteins / GTP-binding – GTP
Intracellular
receptor to cellular target; allows new gene proteins with GTPase activity (Ha-
transducers
expression, or modifying levels of expression, ras, Ki-ras, N-ras)
largest class of oncogenic proteins PLC-related protein – contains src-
related regions homologous to PLC
(crk)
Nuclear transcription directly affect nuclear functions [transcription]; might be involved
factors and nuclear in RNA splicing; bind to DNA secquences in promoters and jun, fos, N-myc, myb, p53, ski
membrane proteins enhancers of genes

Sites of Oncogenic Intervention / Mimicry of Growth-Control Proteins

1) Protein itself as a mimic – interaction with suitable receptor = cell growth (autocrine fashion)
2) Mutation of occupied GF receptor – mitogenic signal even without exogenous stimuli
3) Act on intracellular growth control pathway – no need for exogenous stimuli

Protooncogenic Activation Mechanisms

Mechanis Description Examples
m
causes excessive  ras family – difference in 12th codon (Gly  Val) = oncogene product p21
Point
expression or protein – role in cellular responses to hormones and drugs  ↓ GTPase
mutatio
abnormal protein activity
n
synthesis  implicated with epithelial tumors, sarcomas, erythroleukemia
Genetic
rearran
proximity of
gement  Burkitt’s lymphoma: c-myc from Chr8  Chr14 = enhanced heavy chain
chromosomal
/ immunoglobulin production
breakpoints to
Chrom  Chronic myelogenous leukemia: c-abl from Chr9  inserts into bcr gene @
known loci of
osomal Chr 22  bcr-abl hybrid gene (Philidelphia chr)  growth of leukemia cells
oncogenes
translo
cation
increase number in
Gene
gene copy number
amplific  Neuroblastoma – N-myc gene with replication errors
leads to over-
ation
expression
gene
Promot
rearrangement
er and
causes
enhanc  myc gene – activated by upstream insertion of viral LTR (promoter) or by
protooncogene to
er up/downstream insertion of provirus in myc in reverse direction (enhancer)
be enhanced or
insertio
fused with another
n
gene
Deletio
n of loss of genes
tumor whose expression
suppre inhibits  Retinoblastoma – deletion of RB gene in Chr 13
ssor transformation  Colorectal cancer – deletion of p53 (guardian of the genome, controls
genes / leading to apoptosis) in Chr17
anti- neoplastic
oncoge conversion
nes

Causes of Activation
Cause Effect Examples
Radiation breaks DNA strands UV, X-ray, atomic particles
Electrophillic reactivity  Natural or man-made; food and chemical
Chemicals
attack DNA pollutants
Aflatoxin – moldy peanuts Benzopyrene –
grilled foods
Carcinogens affinity for proliferating cells
Diethylnitrosamine – whiskey Vinyl chloride –
plastic
interferes with DNA
Others drugs, chemotherapeutics, repeated trauma
replication & repair
integrates own DNA with
Viruses RNA / DNA tumor viruses
host DNA
retroviruses, single
RNA Tumor/
stranded DNA genome, HTLV, HIV
Oncorna Viruses
reverse transcriptase

Tumor Viruses
  Rous sarcoma virus – in chickens, retrovirus
 Contains oncogene src + 3 genes in retroviruses
o gag – viral core proteins
o pol – reverse transcriptase and integrase
o env – surface (envelope) glycoproteins
 retroviral oncogenes (v-src) has cellular counterparts (c-src) with introns = v-src probably obtained from host cells
 intronless RNA genome replicates via reverse transcription into DNA, proviral DNA integrates into host genetic material  transcribed
 if inserted near oncogene of host  oncogene becomes part of retroviral genome  transcribed and propagated
 LTRs (long terminal repeats) – 100-200 base pairs at ends of inserted proviral segment serve as molecular control elements in activation of
cellular oncogene
 Retrovirus family – adult T-cell leukemia / lymphoma (Human T-lymphocyte virus); Kaposi’s sarcoma (HIV)
 Polyoma viruses, adenoviruses, HepaB virus, Epstein-Barr virus
 Propagated in the wild, not dependent in cancer production
o SV40 virus – activates host cell for DNA replication  uses host proteins to replicate and transcribe its own genome
 Viral DNA, if it failed to replicate, may act as an oncogene, stably incorporated into host genome
 Viral DNA protein products can deactivate tumor suppressor genes (T antigen with RB protein gene)
 No cellular counterparts
 Papiloma virus family – warts, uterine cervical carcinoma
 Herpes virus family – Burkitt’s and nasopharyngeal lymphoma
 Hepdna virus family – liver carcinoma (hepatocellular)

Clinical Application
 Potential Diagnostic Uses
o Screening for malignancy and cancer susceptibility via RFLP
o Genetic counseling pre- or post-natally
o Gene amplification as useful tumor marker
o Tumor marker production from oncogene products
o Identification of cancer-prone individuals
 Potential Therapeutic Applications
o Anti-oncogene therapeutics – anti-idiotype monoclonal antibodies against oncogene growth factors and cell surface receptors
o Anti-oncogene nucleic acid therapeutics
o Cancer vaccines