Cancer Genetics 2 Flashcards
What is apoptosis?
Programmed cell death
- when DNA damage is too severe to repair
- Cells Balt progress through cell cycle
- prevents cancer by removing cells with DNA damage (mutations)
- Cells with DNA damage are NOTallowed to replicate (divide) and mutation is not passed on to next generation of somatic cells
What is the role of Bcl-2 in apoptosis?
- Bcl-2 protein inhibits apoptosis and Bax protein is pro-apoptotic (triggers apoptosis )
- When there is Bcl-2, Bax is inhibited and there is no apoptosis ; Bcl-2 inhibits Bax
- When there is stress (DNA damage ), a Bcl-2 is inactivated. Bax activates caspases which triggers apoptosis
Describe Bcl-2 overexpression in cancer
- increased production of Bcl-2 —> inhibition of apoptosis (reduced cell death)
- As a result, cells with DNA damage continue to divide (hallmark of cancer)
What does tumor suppressor genes encode for?
Code for proteins that inhibit cell cycle and initiate apoptosis
Describe tumor suppressor gene mutations
- these are loss of function mutations
- Mutations in both copies of tumor supressor gene are necessary for cancer development: ‘two hit hypothesis’
- Examples are RBC and p53
- Arrest cell cycle at G1 phase and prevent cell progression to S phase (active at G1-S checkpoint)
Outline the two hit hypothesis
Two normal copies of Rb—> first hit (somatic mutation) —> Second hit in same somatic cell (somatic mutation). Both copies are lost —>
Complete loss of tumor supressor activity
- no functional Rb protein
- development of retinoblastoma
Explain retinoblastoma as tumor suppressor gene
Rb(retinoblastoma) functions at G1-S checkpoint
- In G1 phase, RBC is bound to E2F
- End of G1 phase, Rb is phosphorylated by CDKs
- Phosphorylated Rb cannot bind to E2F (transcription factor).
- E2F is free to stimulate transcription of S phase genes
- Cells move from G1-S phase (cell division progresses)
- In retinoblastoma, there is a mutant RBC protein that no longer binds to E2F, resulting in uncontrolled cell division
What is the role of Rb in cell cycle?
- Non phosphorylated Rb bound to E2F in G1 phase
- Cyclin CDKs phosphorylates Rb to release E2F and is at the end of the G1 phase
- E2F migrate to nucleus to induce transcription
- Protein factors for cell progression are produced
How does retinoblastoma cause uncontrolled cell division?
In retinoblastoma, there is a mutant RBC protein (or no Rb protein) that no longer binds to E2F , resulting in uncontrolled cell division
What are the TP53(p53) tumor suppressor gene?
TP53 (p53) tumor-suppressor gene
- Encodes transcription factor that represses or stimulates transcription of different genes
- Controls cell cycle at G1/S checkpoint
- Mutated in 50% of cancers
What is the function of p53?
- Present in low concentration at end of G1 phase. (No DNA damage )
- Scans genome for DNA damage
- When NO DNA damage, allows cell to enter S phase
- p53 is degraded
What is the function of p53 tumor-suppressor protein?
-When DNA damage is present, increased p53 levels
- p53 causes
- Arrest of cell cycle in G1 phase (activation of G1/S checkpoint)
- Activates DNA repair proteins
- If DNA damage is extensive, p53 activates apoptosis (cell death)
- p53 is hence known as ‘guardian of the genome’ or ‘molecular policeman’
Describe p53 and cell cycle
p53 is active at G1-S checkpoint
- Cells lacking p53 are unable to undergo apoptosis
- Cells with DNA damage are unable to undergo apoptosis
- Cells with DNA damage (mutations) divide and increase risk of cancer
- Cellular stress events that increase p53 levels
- DNA damage
- Double-stranded breaks in DNA
- Presence of DNA-repair intermediates due to UV light
Explain familial inherited cancer predisposition
Tumor suppressor mutations run in families and increase risk of cancer
- Autosomal dominant transmission
- Familial breast cancer (BRCA-1 or BRCA-2 mutation)
- Familial retinoblastoma (RBC gene mutation)
- Li Fraumeni syndrome (p53 mutation)
- Familial Adenomatous Polyposis (APC gene mutation)
What happens when familial inherited cancer is passed down?
Mutation is passed from affected parent to child (germline): first hit
Mutation in second copy occurs during life (somatic mutation): second hit
Explain the two hit hypothesis: inherited retinoblastoma
- First hit inherited from affected parent(germline)- cells are heterozygous (they have a mutant copy and a wild type normal copy)
- Second hit in a somatic cell both copies are lost- Cancer cell shows ‘loss of heterozygousity’ (both copies are mutant)
- Complete loss of tumor suppressor activity
- No functional Rb protein
- Development of retinoblastoma
How does loss of heterozygosity contribute to cancer?
- second wild type (normal) allele is mutated in tumor tissue
- essential first-step in expression of inherited cancers
- Additional mutations necessary for malignancy (familial adenomatous polyposis)
What mechanisms result in loss of heterozygosity (loss of second copy)?
- Spontaneous deletion of the second copy
- Point mutation resulting in an inactive protein
- Epigenetic changes: methylation of gene resulting in reduced expression of gene (no tumor suppressor protein formed)
