Download oncogenes

Oncogenes and tumour suppressor genes
oncogenes
Tumour
suppressor
genes
Oncogenes
• Genes known as proto-oncogenes code for
proteins that stimulate cell division
• mutated forms, called oncogenes, cause
stimulatory proteins to be overactive, with the
result that cells proliferate excessively
• gain of function mutations
Oncogenes
gain of function mutations
Some acronyms!
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•
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Myc
Sis
Erb
Src
Ras
Yes
• Abl
• Fos
• jun
Myelocytomatosis
Simian sarcoma
Erythroblastoma
Rous sarcoma virus
Rat sarcoma
2 viruses Y73 & ESH sarcoma, isolated from
a chicken owned by Mr. Esh
Abelson murine leukaemia virus
Finkel biskis jinkins reilly mouse sarcoma
junana
Activation of proto-oncogenes
• Viral insertion
• Chromosomal rearrangements
– Altered regulation
– Fusion genes
• Gene amplification
• Point mutations
• Loss of degradation signals
Viral insertion
Chromosomal rearrangements – altered regulation
Burkitts lymphoma
All patients show t(8:14)
translocation of the
immunoglobulin gene on
chromosome 14 to the c-myc
oncogene locus on
chromosome 8
c-myc is under regulatory
control of IgH resulting in
overexpression of the
oncogene
Chromosomal rearrangements - fusion gene
Chronic Myelogenous Leukaemia
Translocation t(9:22)
Abl-bcr fusion gene encodes a constitutively active protein tyrosine
kinase, which affects cell cycle, adhesion and apoptosis
point mutations
Point mutations in ras,
implicated in bladder
carcinoma
e.g. GGC to GTC (G12V)
Gene amplification
Metaplastic breast carcinomas (MBCs)
account for less than 1% of all
invasive mammary carcinomas.
Approximately 70–80% of metaplastic
breast carcinomas overexpress the
epidermal growth factor receptor
(EGFR).
Human epidermal growth factor
receptor (HER2)
EGFR gene amplification in MBC (>5
signals per nucleus). Note the bizarre
neoplastic cell with more than
10 copies of EGFR.
Loss of degradation signals
Epstein–Barr virus (EBV)
is a human herpesvirus
associated with lymphoid
and epithelial
malignancies.
Three viral proteins,
EBNA1, LMP-1 and -2A,
constitutively activate cmyc oncogene by
decreasing ubiquitindependent proteolysis of
this protein and
upregulate compensatory
pathways in Burkitt’s
lymphomas.
Seminars in Cancer Biology Volume 13, Issue 1 , February 2003, Pages 69-76
Growth factor signalling and oncogenes
Cell Cycle Control is through the effects
of growth factors which interact with
membrane-bound glycoprotein
receptors that transduce the message
via a series of intracellular signals that
promote or inhibit the expression of
specific genes.
Oncogenes and the cell cycle
GENES
Further examples of oncogenes
Genes for growth factors or their receptors
PDGF
Codes for platelet-derived growth factor. Involved in glioma (brain cancer)
erb-B
Codes for the receptor for epidermal growth factor. Involved in
glioblastoma (brain cancer) and breast cancer
erb-B2 Also called HER-2 or neu. Codes for a growth factor receptor. Involved in
breast, salivary gland and ovarian cancers
RET
Codes for a growth factor receptor. Involved in thyroid cancer
Genes for cytoplasmic relays in stimulatory signaling pathways
Ki-ras
Involved in lung, ovarian, colon and pancreatic cancers
N-ras
Involved in leukemias
Genes for transcription factors that activate growth promoting genes
c-myc
Involved in leukemias and breast, stomach and lung cancers
N-myc Involved in neuroblastoma (a nerve cell cancer) and glioblastoma
L-myc Involved in lung cancer
Genes for other molecules
Bcl-2
Codes for a protein that normally blocks apoptosis. Involved in follicular B
cell lymphoma
Bcl-1
Also called PRAD1. Codes for cyclin D1, a stimulatory component of the
cell cycle clock. Involved in breast, head and neck cancers
MDM2
Codes for an antagonist of the p53 tumor suppressor protein. Involved
sarcomas (connective tissue cancers) and other cancers
References