Determinants of 14-3-3σ Protein Dimerization and Function in Drug and Radiation Resistance

Li, Zhaomin; Peng, Hui; Qin, Li; Qi, Jing; Zuo, Xiaobing; Liu, Jing Yuan; Zhang, Jian-Ting

doi:10.1074/jbc.m113.467753

Cited by 15 publications

(16 citation statements)

References 32 publications

(40 reference statements)

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“…Others and we have also shown that 14-3-3σ helps arrest cells in G2/M phase following DNA-damages (9,11,25). To determine how 14-3-3σ regulates cell cycle progression, we first analyzed cell cycle distribution of MiaPaCa-2/σ and BxPC-3/Sh-σ cells in comparison with their respective control cells following IR.…”

Section: Resultssupporting

confidence: 53%

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14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

Chen

Dong

et al. 2017

Molecular Cancer Research

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14-3-3σ has been implicated in the development of chemo and radiation resistance and in poor prognosis of multiple human cancers. While it has been postulated that 14-3-3σ contributes to these resistances via inhibiting apoptosis and arresting cells in G2/M phase of the cell cycle, the molecular basis of this regulation is currently unknown. In this study, we tested the hypothesis that 14-3-3σ causes resistance to DNA-damaging treatments by enhancing DNA repair in cells arrested in G2/M phase following DNA-damaging treatments. We showed that 14-3-3σ contributed to ionizing radiation (IR) resistance by arresting cancer cells in G2/M phase following IR and by increasing non-homologous end joining (NHEJ) repair of the IR-induced DNA double strand breaks (DSBs). The increased NHEJ repair activity was due to 14-3-3σ-mediated up-regulation of Poly(ADP-ribose) polymerase 1 (PARP1) expression that promoted the recruitment of DNA-PKcs to the DNA damage sites for repair of DSBs. On the other hand, the increased G2/M arrest following IR was due to 14-3-3σ-induced Chk2 expression. Implications These findings reveal an important molecular basis of 14-3-3σ function in cancer cell resistance to chemo/radiation therapy and in poor prognosis of human cancers.

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Section: Resultssupporting

confidence: 53%

“…Cell cycle analysis was performed as previously described (25). Briefly, 2×10 5 cells were seeded in 6-well plates followed by IR treatment.…”

Section: Methodsmentioning

confidence: 99%

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

Chen

Dong

et al. 2017

Molecular Cancer Research

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“…Survivin has one dimerization core unit consisting of four residues: Leu 98 and Phe 101 from one chain and same residues from another chain. This dimerization core entity is further validated by its water-exchange rate determined via 20-ns water explicit MD simulation as previously described (27,28). A sphere of 6 Å in radius was drawn from the center in the mass of the core.…”

Section: Molecular Dynamics Simulation Analysis Of Water Traffickingmentioning

confidence: 99%

“…Because survivin exists as a homodimer, we hypothesized that a small-molecule compound that inhibits survivin dimerization may promote survivin degradation via the proteasome and, thus, eliminates the protein and leads to spontaneous apoptosis. We recently developed a novel strategy to identify interfacial dimerization core units critical for homodimerization (27,28). Using this strategy, we tested the above hypothesis by first identifying the dimerization core residues critical for survivin dimerization followed by in silico screening for inhibitors targeting the critical core residues as well as in vitro and cell-based assays.…”

Section: Introductionmentioning

confidence: 99%

Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors

Dong

Liu

et al. 2016

Cancer Research

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Many oncoproteins are considered undruggable because they lack enzymatic activities. In this study, we present a small-molecule-based anticancer agent that acts by inhibiting dimerization of the oncoprotein survivin, thereby promoting its degradation along with spontaneous apoptosis in cancer cells. Through a combination of computational analysis of the dimerization interface and in silico screening, we identified one compound that induced proteasome-dependent survivin degradation. Analysis of a set of structural analogues led us to identify a lead compound (LQZ-7F), which was effective in blocking the survival of multiple cancer cell lines in a low micromolar concentration range. LQZ-7F induced proteasome-dependent survivin degradation, mitotic arrest, and apoptosis, and it blocked the growth of human tumors in mouse xenograft assays. In addition to providing preclinical proof of concept for a survivin-targeting anticancer agent, our work offers novel in silico screening strategies to therapeutically target homodimeric oncogenic proteins considered undruggable. Cancer Res; 76(2); 453-62. Ó2016 AACR.

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“…They mediate their physiological effects by binding to other proteins, modulating their (clients’) subcellular localization, enzymatic activity, or their ability to interact with further proteins 7 . For example, the σ isoform has been implicated in breast cancer 8 and is necessary for proper G 2 checkpoint function 9 . As one of the most important “hub” proteins with at least 200–300 interaction partners, the 14-3-3 proteins are an especially fruitful case for PPI intervention 10 .…”

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confidence: 99%

Revealing the binding modes and the unbinding of 14-3-3σ proteins and inhibitors by computational methods

Cao

et al. 2015

Sci Rep

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The 14-3-3σ proteins are a family of ubiquitous conserved eukaryotic regulatory molecules involved in the regulation of mitogenic signal transduction, apoptotic cell death, and cell cycle control. A lot of small-molecule inhibitors have been identified for 14-3-3 protein-protein interactions (PPIs). In this work, we carried out molecular dynamics (MD) simulations combined with molecular mechanics generalized Born surface area (MM-GBSA) method to study the binding mechanism between a 14-3-3σ protein and its eight inhibitors. The ranking order of our calculated binding free energies is in agreement with the experimental results. We found that the binding free energies are mainly from interactions between the phosphate group of the inhibitors and the hydrophilic residues. To improve the binding free energy of Rx group, we designed the inhibitor R9 with group R9 = 4-hydroxypheny. However, we also found that the binding free energy of inhibitor R9 is smaller than that of inhibitor R1. By further using the steer molecular dynamics (SMD) simulations, we identified a new hydrogen bond between the inhibitor R8 and residue Arg64 in the pulling paths. The information obtained from this study may be valuable for future rational design of novel inhibitors, and provide better structural understanding of inhibitor binding to 14-3-3σ proteins.

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Determinants of 14-3-3σ Protein Dimerization and Function in Drug and Radiation Resistance

Cited by 15 publications

References 32 publications

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

14-3-3σ Contributes to Radioresistance By Regulating DNA Repair and Cell Cycle via PARP1 and CHK2

Effective Targeting of the Survivin Dimerization Interface with Small-Molecule Inhibitors

Revealing the binding modes and the unbinding of 14-3-3σ proteins and inhibitors by computational methods

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