Not inclusive definition: DNA repair
proteins do not negatively regulate cell cycle
Two Major Tumor
Suppressors that we have discussed:
pRb;
inhibits E2F-dependent cell cycle transcription
p53;
activated by DNA damage to enforce cell cycle arrest and/or cell death
In many familial
cancer syndromes, affected individuals inherit a single functional
copy
of a tumor suppressor gene, and this functional copy is inactivated.
Tumor Suppressors
can be inactivated by several mechanisms
A
second mutation
Promoter
methylation
Loss
of Heterozygosity (LOH)
DNA Tumor Virus Oncoproteins
Cells
inherit a single centrosome through mitosis and cytokinesis
this
centrosome must be duplicated exactly once to form the mitotic spindle
Centrosome
abnormalities are seen in most human tumors
Centrosome
abnormalities cause mitotic abnormalities
High risk Human
Papiloma Virus (HPV) inactivates pRb and p53
Integration
of virus (happens only rarely) misregulates viral gene expression
only
E6 and E7 are expressed
E6 and E7 cooperatively transformation cells
Overexpression
of E6 and E7 allow accumulation of DNA damage
E6
inhibits p53, cells cannot halt cell cycle in response to DNA damage
E7
inhibits pRb, rapid S-phase progression may actually cause damage
High risk HPV
(i.e. HPV16 and HPV18) causes over-duplication of centrosomes
Extra
centrosomes cause mitotic defects:
multi-polar
spindles, unaligned chromosomes, lagging chromosomes
E7-expressing
cells accumulate extra centrosomes before becoming aneuploid
Inhibition
of pRB allows E2F-dependent expression of Cdk2, cyclins E and A
all
accelerate centrosome duplication
E7-expressing
cells over-duplicate centrosomes within a single cell cycle
E6-expressing
cells become aneuploid before accumulating extra centrosomes
Inhibition
of p53 causes cells to fail to arrest in G2 due to DNA damage
this
leads to frequent failure of cytokinesis, producing polyploidy cells
Inhibition
of p53 allows cells that failed in cytokinesis to enter the cell cycle
these
cells inherit two nuclei (polypoloidy) and TWO centrosomes
Inhibition
of p53 therefore indirectly causes accumulation of centrosomes
E6 and E7
cooperate to transform cells
E6
inhibits p53, producing polyploidy cells
(extra copies of all chromosomes and two
centrosomes)
E7
inhibits pRb, allowing overduplication of centrosomes
Extra
Centrosomes Cause Mitotic Abnormalities in Polyploid Cells
This
causes aneuploidy, which can drive transformation
(by
unbalancing positive and negative cell cycle regulators)