Transcript Heterochromatin silencing at p53 target genes by a small viral protein.

Heterochromatin silencing
at p53 target genes by a
small viral protein.
p53
Revealed character as a tumor
suppressor gene in 1989.
Tumor suppressor protein.
Encoded by the TP53 gene.
Preventing tumor development.
Inhibit overexpression of cell.
Regulate to cell cycle.
p53 pathway
E1B-55K
55kDa protein.
Encoded by E1B genomic region
of adenovirus.
Binds to p53 and functionally
inactivates it.
Inhibit cell death by apoptosis.
ONYX-015
Oncolytic adenoviral therapy
Deleted E1B-55K
Trialed as a possible treatment
for cancer.
Be directly injected into a tumor.
Combined with chemotherapy
Result
▶Fig 1. p53 is induced and phosphorylated in ΔE1B-55k
infection but p53 activity is dominantly suppressed.
Result
▶Fig 1. p53 is induced and phosphorylated in ΔE1B-55k infection
but p53 activity is dominantly suppressed.
Result
▶Fig 2. E4-ORF3 inactivates p53 independently of E1B-55k
and p53 degradation.
Result
▶Fig 2. E4-ORF3 inactivates
p53 independently of E1B-55k
and p53 degradation.
Result
▶Fig 3. E4-ORF3 induces
heterochromatin formation
and prevents p53-DNA
binding at endogenous
promoters.
Result
▶Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA
binding at endogenous promoters.
Result
▶Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA
binding at endogenous promoters.
Result
▶Fig 4. E4-ORF3 forms a nuclear scaffold that specifies heterochromatin
assembly and H3K9 trimethylation at p53 target promoters.
Result
▶Fig 4. E4-ORF3 forms a nuclear scaffold that specifies heterochromatin
assembly and H3K9 trimethylation at p53 target promoters.
Result
▶Fig 5. p53 transcriptional targets are silenced selectively in the backdrop of
global transcriptional changes that drive oncogenic cellular and viral
replication.
Result
▶Fig 5. p53 transcriptional targets are silenced
selectively in the backdrop of global
transcriptional changes that drive
oncogenic cellular and viral replication.
Discussion
• p53 induction and phosphorylation is tantamount
to p53 activity, which is the premise for several
cancer therapies.
• Identified, E4-ORF3, directing SUV39H1/2
H3K9me3 heterochromatin assembly at p53 target
promoters to silence p53 activated transcription in
response to genotoxic and oncogenic stress.
Discussion
• All of the known targets of E4-ORF3, PML, the MRN
DNA damage/repair complex and Tif1α are
subverted by tumor mutations.
• Identification of E4-ORF3 changes the fundamental
definition of how p53 is inactivated in adenovirus
infected cells, which is a critical mechanistic insight
that could now enable the rational development of
true p53 tumor selective adenoviral therapies.