PMID: 23472066 RLIMS-P 1 Check other iTextMine results Issue Report
Title
| 1. | 14-3-3ε mediates the cell fate decision-making pathways in response of hepatocellular carcinoma to Bleomycin-induced DNA damage. |
Abstract
| 2. | BACKGROUND: Lack of understanding of the response of hepatocellular carcinoma (HCC) to anticancer drugs causes the high mortality of HCC patients. |
| 3. | Bleomycin (BLM) that induces DNA damage is clinically used for cancer therapy, while the mechanism underlying BLM-induced DNA damage response (DDR) in HCC cells remains ambiguous. |
| 4. | Given that 14-3-3 proteins are broadly involved in regulation of diverse biological processes (BPs)/pathways, we investigate how a 14-3-3 isoform coordinates particular BPs/pathways in BLM-induced DDR in HCC. |
| 5. | METHODOLOGY/PRINCIPAL FINDINGS: Using dual-tagging quantitative proteomic approach, we dissected the 14-3-3ε interactome formed during BLM-induced DDR, which revealed that 14-3-3ε via its associations with multiple pathway-specific proteins coordinates multiple pathways including chromosome remodeling, DNA/RNA binding/processing, DNA repair, protein ubiquitination/degradation, cell cycle arrest, signal transduction and apoptosis. |
| 6. | Further, "zoom-in" investigation of the 14-3-3ε interacting network indicated that the BLM-induced interaction between 14-3-3ε and a MAP kinase TAK1 plays a critical role in determining cell propensity of apoptosis. |
| 7. | Functional characterization of this interaction further revealed that BLM triggers site-specific phosphorylations in the kinase domain of TAK1. |
| 8. | These BLM-induced changes of phosphorylations directly correlate to the strength of the TAK1 binding to 14-3-3ε, which govern the phosphorylation-dependent TAK1 activation. |
| 9. | The enhanced 14-3-3ε-TAK1 association then inhibits the anti-apoptotic activity of TAK1, which ultimately promotes BLM-induced apoptosis in HCC cells. |
| 10. | In a data-dependent manner, we then derived a mechanistic model where 14-3-3ε plays the pivotal role in integrating diverse biological pathways for cellular DDR to BLM in HCC. |
| 11. | CONCLUSIONS: Our data demonstrated on a systems view that 14-3-3ε coordinates multiple biological pathways involved in BLM-induced DDR in HCC cells. |
| 12. | Specifically, 14-3-3ε associates with TAK1 in a phosphorylation-dependent manner to determine the cell fate of BLM-treated HCC cells. |
| 13. | Not only individual proteins but also those critical links in the network could be the potential targets for BLM-mediated therapeutic intervention of HCC. |
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Legend: SUBSTRATE KINASE INTERACTANT SITE GENE MIRNA ANOMALY EXPRESSION DISEASE OUTCOME/RESPONSE SR_DRUG DRUG CELL TRIGGER Normalized
Tool: RLIMS-P
| PTM enzyme | Substrate | Site | Sentence |
|---|---|---|---|
| TAK1 (O43318) | 7 |