Treatment of C Flashcards
How did we learn about tumour-suppressors?
The risk of developing breast cancer in healthy individual is around 5-10%.
However some individuals are prone to increased risk of developing breast or ovarian cancer.
Individuals inheriting mutations in BRCA1/2 have a 50-80% lifetime risk of developing breast cancer and 30-50% lifetime risk of developing ovarian cancer.
Caretakers and gatekeepers How many categories are tumour suppressor are divided in ?
Tumour suppressors are divided in two categories: • Caretakers are tumour suppressors involved in DNA damage repair
- Gatekeepers are tumour suppressors involved in cell death and cell cycle arrest
- Together they prevent accumulation of mutations and therefore cancer development
Li Fraumeni Germaline
-Li-Fraumeni syndrome is a genetic disease characterized by germline mutations in p53 which lead to a wide range of cancers. It is autosomal dominant disease. Patients have 25 fold increased risk of developing cancer before they are 50 years old, compared to the general population.
What is P53 ?
P53 is a gate-keeper
P53 exerts its tumour suppressor effects by activating four main responses:
- 1) cell cycle arrest
- 2) DNA repair
- 3) Apoptosis
- 4) Inhibition of angiogenesis
P53-induced transcription of p21 gene arrests the cell cycle by inhibiting Cdks
This mechanism depends on induction of expression of cell cycle inhibitor p21 (encoded by cdkn1a gene).
P21 inhibits cyclin D-cdk complexes and cause a pause in the G1to S phase of the cell cycle thus giving time for the DNA to be repaired (and cdc2-cyclin B for arrest between G2 and M phase).
Other p53-dependent transcriptional changes promote cell death if DNA damage is irreversible or excessive
Why elephants do not get cancer?
12 copies of the tumor suppressor TP53!!
Germline mutations in pRB Retinoblastoma
- Retinoblastoma is a rare childhood cancer with a worldwide incidence of 1 in 20000.
- About 40% of cases are familial and 60% are sporadic.
RB is a gatekeeper that regulates the G1-S checkpoint of the cell cycle
In absence of a growth signal RB is hypophosphorylated and binds E2F.
- Binding of RB to E2F leads to sequestration of E2F and blocks its transactivation domain, preventing it to bind to transcription factors.
- Phosphorylation of RB releases E2F, leadinto expression of E2F target genes.
Human Papilloma Virus (HPV) and inactivation of p53 and pR
-E6 and E7 are oncoproteins produced by HPV -E6 binds and inactivates p53, blocking apoptosis
-E7 binds pRB. This binding causes release of E2F and entry into the cell cycle. The overall effect is enhanced proliferation.
Polager et al.
p53 and E2F partners in life and death. Nature Reviews Cancer 2009
A vaccine has now been developed. It protects against HPV.
BRCA1 and BRCA2 are caretakers
Breast Cancer susceptibility gene 1 and 2 (BRCA1 and BRCA2) are tumour suppressors deputed to the maintenance of genomic stability and control of cell growth.
• BRCA1 and BRCA2 proteins are involved in the DNA double strand break (DSB) via homologous recombination.
Mutations in the genes coding for BRCA1 and BRCA2 raise the risk of developing breast cancer and ovarian cancer. These mutations exhibit an autosomal dominant pattern.
What do Mutations in APC?
Mutations in APC induces Familial adenomatous polyposis, an inherited cancer susceptibility trait, that greatly increases risk of colon cancer
APC gene mutations affect Beta-catenin
Beta-catenin is a cytosolic protein which is also present at adherens junctions, where it cannot activate gene transcription.
The Wnt signaling pathways ?
The Wnt pathway is activated selectively in proliferating cells of colon epithelia
are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. .The noncanonical planar cell polarity pathway regulates the cytoskeleton that is responsible for the shape of the cell.
APC gene mutations affect “Wnt” signalling
Growth Signals from Proteins ?
Growth signals from Wnt proteins are transmitted when b-catenin accumulates.
Target genes include Myc!
Epithelial Cells
In epithelial cells, b-catenin is:
Mainly captured at the cell membrane by adherens junctions, where it cannot activate cell cycle but participates in cell/cell contact
Phosphorylated in the cytosol with help of APC, and degraded, so it cannot activate Myc and thus cell cycling
