FINAL EXAM -- TSGs slides 11 Flashcards
Normal cells must acquire at least 4 distinct mutational or epigenetic events to…
bypass proliferative control. the event alter critical signal transduction pathways.
What are the Three categories in groups of cancer-associated genes?
- Oncogenes
- Tumor supressor genes
- Genes responsible for maintaining genome stability. ( sometimes this is grouped into TSGs)
Oncogenes
- Typically, a mutant form of a normal gene (protooncogene) involved in cell growth and proliferation; stimulates the cell cycle
- Gain of function mutations; constitutively active or overexpressed versions
- Mutation behaves as a dominant allele in its ability to confer malignant
properties - Rarely transmitted through the germ line
Tumor Suppressor genes
- Inhibut cell cycle progression, suppress growth
- Loss of function mutations confer malignant properties
- Mutant alleles are typically recessive
- Can be passed through the germline and cause inherited forms of cancer predisposition in humans
Genes responsible for Maintaining genome stability
- Primarily involved in cellular processes that maintain basal levels of genomic or chromosomal stability
The proficiency of a cell in accurately repairing various forms of genomic insult depends on its ability to:
- Sense acute genomic damage, usually in the form of single or double-strand DNA breaks
- Mobilize specific repair enzymatic complexes to sites of DNA damage
What is a major contributor to genomic instability?
The inactivation of TP53, which encodes the p53 transcription factor, is a major contributor.
Tumor Suppressor Genes can encode proteins that are functionally integrated into pathways that:
- Prevent unscheduled cell proliferation
- Stimulate cell death
- Trigger the induction of permanent cell cycle arrest
What is the orchestration of cell cycle checkpoints?
This ensures that there is faithful cell division under normal or stress-induced conditions.
TSGs
- May act as negative regulators of oncogenes
- become involved in tumor progression only after some loss of gene function. This requires the inactivation of both parental alleles in a single cell
Common Inactivating mechanisms of TSGs include
- Deletions and nonsense mutations
- Missense mutations ( mutations at a catalytic site)
- Methylation-mediated gene silencing
these are all examples of frame shift mutations.
Oncogene (dominant relationship)
- Dominant
- Growth without regulation
ABNORMAL GROWTH
Tumor Suppressor Gene - (recessive relationship)
- Recessive
- Loss of growth inhibitor
Abnormal Growth
Tumor suppressor gene - Haploinsufficent
- Lower gene dose
Abnormal Growth
Knudson’s two-hit hypothesis
- Model used to explain how recessive mutation in TSGs contributed to the carcinogenic process
- The mutations that can be inherited could be a first hit at birth
What are some inhibitors in growth stimulation and proliferation pathways?
- Phosphatases - off switch
- PTEN (lipid phosphatase)
- CDK inhibitors - arrest cell cycle
- BRCA1(DNA damage regulation) and BRCA2
- APC - Wnt pathway suppressor
- E-cadherin - mesenchymal transition
- RB1 (pRB)
- TP53 (p53)
BRCA1 and BRCA2
- breast cancer 1 and 2
- unrelated proteins
- help repair damaged DNA or destroy cells if DNA cannot be repaired
pRB (retinoblastoma)
- Functions at R checkpoint; determines whether cell continues in cell cycle
Dynamics of retinoblastoma formation
-Familial form - bilateral retinoblastoma
- Sporadic form - unilateral retinoblastoma
Familial retinoblastoma
- born with mutant allele so on the first somatic mutation you will have two mutant alleles with will lead to bilateral disease.
- it is heritable if it is in the germ line
Sporadic retinoblastoma
-Upon the first somatic mutation you get one mutant allele. Then upon the second somatic mutation, you will get two mutant alleles leading to unilateral disease
Incipient (in an initial stage; beginning to happen or develop) cancer cells eliminate
wild-type copies of TSGs by a variety of mechanisms
becoming homozygous for the mutation through
- mitotic recombination
- Loss of heterozygosity
Mitotic recombination
Recombination between homologous chromosomal arms occurs during somatic cell proliferation, often during the G2 phase of
the cell cycle (rather than during mitosis
