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

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Presentation on theme: "Heterochromatin silencing at p53 target genes by a small viral protein."— Presentation transcript:

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

2 p53  Revealed character as a tumor suppressor gene in  Tumor suppressor protein.  Encoded by the TP53 gene.  Preventing tumor development.  Inhibit overexpression of cell.  Regulate to cell cycle.

3 p53 pathway

4 E1B-55K  55kDa protein.  Encoded by E1B genomic region of adenovirus.  Binds to p53 and functionally inactivates it.  Inhibit cell death by apoptosis.

5 ONYX-015  Oncolytic adenoviral therapy  Deleted E1B-55K  Trialed as a possible treatment for cancer.  Be directly injected into a tumor.  Combined with chemotherapy

6 Result ▶ Fig 1. p53 is induced and phosphorylated in ΔE1B-55k infection but p53 activity is dominantly suppressed.

7 Result ▶ Fig 1. p53 is induced and phosphorylated in ΔE1B-55k infection but p53 activity is dominantly suppressed.

8 Result ▶ Fig 2. E4-ORF3 inactivates p53 independently of E1B-55k and p53 degradation.

9 Result ▶ Fig 2. E4-ORF3 inactivates p53 independently of E1B-55k and p53 degradation.

10 Result ▶ Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA binding at endogenous promoters.

11 Result ▶ Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA binding at endogenous promoters.

12 Result ▶ Fig 3. E4-ORF3 induces heterochromatin formation and prevents p53-DNA binding at endogenous promoters.

13 Result ▶ Fig 4. E4-ORF3 forms a nuclear scaffold that specifies heterochromatin assembly and H3K9 trimethylation at p53 target promoters.

14 Result ▶ Fig 4. E4-ORF3 forms a nuclear scaffold that specifies heterochromatin assembly and H3K9 trimethylation at p53 target promoters.

15 Result ▶ Fig 5. p53 transcriptional targets are silenced selectively in the backdrop of global transcriptional changes that drive oncogenic cellular and viral replication.

16 Result ▶ Fig 5. p53 transcriptional targets are silenced selectively in the backdrop of global transcriptional changes that drive oncogenic cellular and viral replication.

17 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.

18 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.


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