Lecture 7: Evading growth suppressors Flashcards
What happens when RB1 is hyperphosphorylated by the Cycline D/CDK4,6 complex ?
It liberates E2F which activates DNA replication and cell cycle genes
What is the role of CKI (CDK inhibitors) ?
It inhibits the phosphorylation of RB1 and E2F represses target genes
What is TGF-β and what is its role ?
It’s a transforming growth factor and it blocks the cell cycle by inducing several CDK inhibitors
What is transformed growth ?
It refers to uncontrolled cell proliferation ((ability to survive without
adhesion to ECM))
Give the TGF-β - Smad pathway
- TGF-β binds to type II receptor
- Type I receptor binds this receptor-ligand complex
- Type II phosphorylate type I
- Smad2/3 are phosphorylated and bind Smad4 (becoming co-Smad)
- Co-smad enter the nuclei to regulate target genes
What determines the target gene of TGF-β?
co-factors (co-activator and co-repressor)
(les CKI released sont différents suivant le co-factor)
Give the tumor supression function of TGF-β in:
1) epithelial cells
2) stromal cells
1) Cell cycle arrest, senescence, or even death
2) Inhibition of secreted oncogenic factors
what is the neurofibromatosis type I syndrome?
- autosomal dominant syndrome that affects neural crest derivatives
- caused by inherited heterozygous mutations in neurofibromin-1 (NF1) diagnosed by “café au lait” spots (melanocyte pigmentation defects)
- mutation of the residual copy of NF1 (loss of heterozygosity) in Schawann cells provokes neurofibromas
what are neurofibromas?
benign tumors that grow on nerves in the body; can give rise to malignant nerve sheath tumors
what is the role of NF1?
GTPase Activating Protein (GAP) that is required to inactivate Ras in Schwann cells; donc loss of NF1 hyperactivates Ras
role of PTEN
- essential to protect against cancer, it dephosphorylates PIP3 which promotes growth and survival by activating AKT substrates
- it is mutated (can be germline or somatic) or downregulated in many cancers
cell fusion experiment outcome
fusion of a normal and a cancer cell, the outcome was a non-tumorigenic hybrid cell
2 forms of retinoblastoma
sporadic: unilateral (appears only in one eye), appears later in childhood (non-heritable)
familial: bilateral (appears in both eyes), predisposes for other cancers (heritable)
can mutations in oncogenes be inherited? why?
no, because it leads to early/aggressive cancer so the embryo dies
can mutations in tumor suppressor genes be inherited? why?
yes, because loss of TSG function by mutation typically requires a second hit in the same gene (loss of heterozygosity) or inhibition of TSG expression
which form of retinoblastoma is more likely to happen?
familial form because one mutant copy of Rb is already inherited from a parent so one single somatic mutation suffices to eliminate Rb whereas you need 2 somatic mutations to develop a sporadic retinoblastoma
2 most frequent mutations in human carcinomas
RB1 and p53
4 ways to evade tumor suppressors
1) mutations
2) epigenetic silencing
3) oncogenic small DNA viruses
4) upregulation of specific inhibitors
RB1 and p53 mutated in small cells in the lungs can lead to 2 diff outcomes
1) small cell lung cancer if mutation in neuroendocrine cell
2) atypical hyperplasia if mutation in Clara cell
p53 tumor suppressive functions
1) cell cycle arrest -> DNA repair
2) apoptosis -> elimination of damaged cells
what is MDM2?
Mouse Double Minute 2 is a E3 ubiquitin ligase that targets p53 for degradation
explain the negative feedback between p53 and Mdm2
p53 transcribes Mdm2 which ubiquitinates p53 for degradation
90% of p53 mutations are in …
its DNA-binding domain and thus block Mdm2 induction
what happens if Mdm2 isn’t transcribed?
-> could cause tumors
elevated levels of (mutant) p53 protein are found in tumors
