Summary Chapter 6 Growth inhibition and tumor suppressor genes

Chapter 6 – Growth inhibition and tumor suppressor genes
Definitions of tumor suppressor genes
Oncogenes; the drivers of tumor cell proliferation
Tumor suppressor genes; inhibitors of tumor cell proliferation

Example:
EGF is present on EGFR  reaction is activated by convert PIP2 into
PIP3 by PI3K due to phosphorylation  proliferation and inhibition of
apoptosis
EGF is gone  reaction need to be stopped by converting PIP3 back to
PIP2 by PTEN (tumor suppressor gene)  proliferation is stopped

If there is a mutation in PTEN the reaction cannot be immediately stopped
when EGF is gone.
It is not a cancer cell yet because the reaction can be stopped in the end
when EGF is gone, but it is very vulnerable.

If there is a mutation in EGFR (proto-oncogene) on top of the mutation in
PTEN it will constantly activate the reaction and the reaction cannot be
stopped anymore. Now we have cancer

Thus, needed for deregulated cell proliferation:
1. Oncogene that is active (mutation in proto-oncogene)
2. Absence of active tumor suppressor gene

Cancer develops
o Sporadical; one tumor, later in life
o Inherited; multiple tumors, sooner in life.

Every healthy cell has 2 copies of a gene
Mutation of an oncogene is dominant so only 1 mutation is
needed to get cancer
Mutation in a tumor suppressor gene is recessive so 2
mutations are needed to get cancer – recessive mutations
support Knudson’s two-hit hypothesis.

How does two-hit hypothesis work?
- Sporadic cancer
First hit: a mutation in one copy of the
tumor suppressor gene -- we still have a
functional copy of the gene so nothing
happens
Second hit: a deletion in the other copy of
the tumor suppressor gene too –
progression to tumor formation (second hit will always be in the small cells as
first hit)
There is a very small changes that this occurs twice in the small cell therefor
occurs sporadic cancer later in life
- Inherited cancer

, First hit: a mutation in one copy of the tumor suppressor gene – we still have a
functional copy of the gene so nothing happens -- now the first hit is inherited
so every cell in the body carries already a mutation
Second hit: a deletion in the other copy of the tumor suppressor gene too –
progression to tumor formation (second hit will always be in the small cells as
first hit)
There is a very large that cancer develops because the first hit is inherited

Remember 4 tumor suppressor genes with their familiar predisposition syndromes
1. RB1 – retinoblastoma (tumors in the eye)
2. p53 – Li, Fraumeni
3. APC – colorectal cancer
4. BRCA – breast/ovarian cancer

The retinoblastoma gene (Rb gene)
RB protein is a regulator of the cell cycle (it
inhibits G1-S transition)
It binds and release transcription factor E2F 
activates target genes  involved cell cycle
The binding of E2F to RB protein is mediated by
phosphorylation and the phosphorylation is
induced by cyclins and cyclin dependent kinases
(Cdk)

Mutations in the RB pathway and cancer
1. Loss of pRB (deletions, frame shift, nonsense
mutation) – E2F is available to drive cell cycle
2. Missense mutation pocket domain pRB (pRB cannot
bind to E2F – E2F is available to drive cell cycle
3. Hyperfosforylation pRB through upstream mutation –
E2F is in unbound situation and is available to drive
cell cycle
4. Sequestration pRB by DNA tumor virus protein (e.g.
HPV E7) (certain viruses produce proteins that can
bind to pRB and thereby releasing E2F) – E2F is
available to drive cell cycle

The p53 pathway (the guardian of the genome)
 Deregulation: sensors: different molecule transfer the
message that there is deregulation to p53 (upstream)
o DNA damage
o Activation of oncogenes
o Cell stress: hypoxia, nucleotide depletion
 Restoration or suicide: effectors (downstream)
o Cell cycle arrest or senescence
o DNA repair
o Apoptosis
o Inhibition of angiogenesis