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
