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PDCD5-regulated cell fate decision after ultraviolet-irradiation-induced DNA damage.

ABSTRACT: Programmed cell death 5 (PDCD5) is a human apoptosis-related molecule that is involved in both the cytoplasmic caspase-3 activity pathway (by regulating Bax translocation from cytoplasm to mitochondria) and the nuclear pathway (by interacting with Tip60). In this study, we developed a mathematical model of the PDCD5-regulated switching of the cell response from DNA repair to apoptosis after ultraviolet irradiation-induced DNA damage. We established the model by combining several hypotheses with experimental observations. Our simulations indicate that the ultimate cell response to DNA damage is dependent on a signal threshold mechanism, and the PDCD5 promotion of Bax translocation plays an essential role in PDCD5-regulated cell apoptosis. Furthermore, the model simulations revealed that PDCD5 nuclear translocation can attenuate cell apoptosis, and PDCD5 interactions with Tip60 can accelerate DNA damage-induced apoptosis, but the final cell fate decision is insensitive to the PDCD5-Tip60 interaction. These results are consistent with experimental observations. The effect of recombinant human PDCD5 was also investigated and shown to sensitize cells to DNA damage by promoting caspase-3 activity.

SUBMITTER: Zhuge C

PROVIDER: S-EPMC3297794 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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PDCD5-regulated cell fate decision after ultraviolet-irradiation-induced DNA damage.

Zhuge Changjing C Chang Ying Y Li Yanjun Y Chen Yingyu Y Lei Jinzhi J

Biophysical journal 20111201 11

Programmed cell death 5 (PDCD5) is a human apoptosis-related molecule that is involved in both the cytoplasmic caspase-3 activity pathway (by regulating Bax translocation from cytoplasm to mitochondria) and the nuclear pathway (by interacting with Tip60). In this study, we developed a mathematical model of the PDCD5-regulated switching of the cell response from DNA repair to apoptosis after ultraviolet irradiation-induced DNA damage. We established the model by combining several hypotheses with ...[more]

PMID: 22261045

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Project description:BackgroundLack of understanding of the response of hepatocellular carcinoma (HCC) to anticancer drugs causes the high mortality of HCC patients. 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. 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.Methodology/principal findingsUsing dual-tagging quantitative proteomic approach, we dissected the 14-3-3? interactome formed during BLM-induced DDR, which revealed that 14-3-3? 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. Further, "zoom-in" investigation of the 14-3-3? interacting network indicated that the BLM-induced interaction between 14-3-3? and a MAP kinase TAK1 plays a critical role in determining cell propensity of apoptosis. Functional characterization of this interaction further revealed that BLM triggers site-specific phosphorylations in the kinase domain of TAK1. These BLM-induced changes of phosphorylations directly correlate to the strength of the TAK1 binding to 14-3-3?, which govern the phosphorylation-dependent TAK1 activation. The enhanced 14-3-3?-TAK1 association then inhibits the anti-apoptotic activity of TAK1, which ultimately promotes BLM-induced apoptosis in HCC cells. In a data-dependent manner, we then derived a mechanistic model where 14-3-3? plays the pivotal role in integrating diverse biological pathways for cellular DDR to BLM in HCC.ConclusionsOur data demonstrated on a systems view that 14-3-3? coordinates multiple biological pathways involved in BLM-induced DDR in HCC cells. Specifically, 14-3-3? associates with TAK1 in a phosphorylation-dependent manner to determine the cell fate of BLM-treated HCC cells. Not only individual proteins but also those critical links in the network could be the potential targets for BLM-mediated therapeutic intervention of HCC.

Dataset Information

PDCD5-regulated cell fate decision after ultraviolet-irradiation-induced DNA damage.

Publications

PDCD5-regulated cell fate decision after ultraviolet-irradiation-induced DNA damage.

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