normal form of the gene involved in induction of cellular proliferation, but in controlled manner
alteration of proto-oncogene -> uncontrolled growth
What are the 3 ways proto-oncogenes can become oncogenes?
1. point mutation - leads to production of protein that functions in an uncontrolled manner resulting in unregulated cell proliferation
2. reduplication or amplification of DNA -> over-expression of proto-oncogene protein product
3. chromosomal translocations -> over-expression of proto-oncogene or structural changes
Oncogenes act in dominant/recessive fashion?
dominant - only 1 allele needs to be altered to produce stimulatory effect on cellular proliferation
Describe the growth factor oncogene.
c-sis proto-oncogene - encodes for beta chain of platelet-derived growth factor (PDGF)
in tumors, this protein is over produced
tumors have receptors for PDGF
result = constant stimulation by growth factor that the tumor itself produces
Describe the growth factor receptors oncogenes.
overexpression of EGFR secondary to amplification of the gene seen in cancer
also can be from point muation
these tumors are often distinct in respect to organ and cell type when compared to amplication
Describe the example of secondary messenger oncogene.
30% of human tumors contain ras oncogenes.
ras proteins = G protein = signal transduction proteins that transduce signals when bind GTP -> hydrolyzes GTP to GDP
mutant ras proteins can hydrolyze GTP to GDP
problem - problems in terminating signal transduction
result - inappropriate stimulatory signals to cell
Describe nuclear transcription factors.
myc proto-oncogenes activate the transcription of a number of genes needed for cellular proliferation
what does tumor suppresor genes do?
regulate the cellular proliferation
What happens when tumor suppresor gene function gets altered?
muations affecting expression or function of tumor suppresssor genes create state of uncontrolled proliferation
Tumor suppressor genes have dominant or recessive mode of action?
recessive - protein product from 1 allele is general sufficient to provide normal control of cellular proliferation
both genes must be altered to produce transformation of cell, but alternation of second allele relatively common
What are the possible ways of eliminating normal Rb gene (tumor supressor gene)?
nondisjunction and duplication
What are the 3 examples of tumor suppressor genes?
Two primary tumor suppressors are the products of what?
the rate limiting step of tumor suppressor gene is production of the first functionally abnormal allele. The remaining normal allele only needs to be ______.
silenced (in contrast to prot-oncogenes which must gaina activity)
relatively high frequencey
once every 103 vs. more than 106 cell divisions for sequence mutation
How is the loss of p53 gene leads to cancer?
function of p53 = arrest cells in G1 when DNA damage has occurred
arrest gives the cell time to repair DNA damage
point mutations alter function allowing unchecked progress through cell cycle
homozygous loss of p53 seen in nearly 1/2 of all malignancies
What is Rb and how does its alteration affects cells?
retinoblastoma produces a protein that prevents cells from leaving G1 or G0 and entering the cell cycle
phosphorylated forms of Rb bind and inactivate transcription factors that are responsible for initiating transcription of cell cycle genes
mutant form of Rb - unable to bind and inactivate transcription factors
tumor develops when both genes are altered
What does Bcl-2 do?
it is the primary control of apoptosis
normal function - prevents cells from undergoing apoptosis
overexpression leads to abnormal survival and proliferation of cells
activations occurs when chromosomal translocation places it near the immunoglobulin heavy gene promoter in Burkitt's lymphoma
"immortalization" of cells that normally undergo apoptosis
What is cellular senescence?
genetic material lost from the end of chromosomes with each division eventually signals senescence (deterioration with age)
abnormal expression of telomerase in cancers prevents this loss -> extended lifespan of cell
what is autosomal dominant hereditatry cancer?
phenotypic expression of increased cancer incidence due to inheritance of single mutated gene allel
pattern of dominant inheritance shows classic Mendelian features with 50% of offspring affected and consistent occurrence in every generation
Tumor suppressor genes associated with _____ mode of action but _____ pattern of inheritance.
Describe hereditary retinoblastoma. Mode of action? Percentage of germline mutation the develop tumor? Percentage that develop bilateral retinoblastoma. Average age for development of tumor? Increase of decrease incidence of other tumors?
1. only single allele needs somatic mutation
2. 80-80% with germline mutation develop tumor
3. 90% develop bilateral retinoblastoma
4. Average age at development of tumor - 2 yr
5. Increased incidence of other tumors
Describe sporadic retinoblastoma. Mode of action? overall incidence? Bilateral?
1. single cell with somatic mutation of Rb plus inactivation of other allele
2. overall inciden < 1/20,000
3. never bilateral
Describe familial Adenomatous Polyposis (FAP). What type of mutation is this? Symptoms? % develop colon cancer by 50 y.o? Average age of diagnosing cancer?
1. germline mutation in APC gene
2. Somatic mutations in unaffected allele causes growth of hundreds of adenomas in young adults
3. 100% develop colon cancer by 50 y.o.
4. average age at diagnosis of cancer = 40 y.o
Describe sporadic colon carcinoma.
1. somatic mutations of both APC genes must occur in a single ceel
2. additional mutations must occur in only one of a few adenomas for cancer to develop