Abstract 3655: Suppression of Plk3 expression by nickel may contribute to lung carcinogenesis
Bibliographic record
Abstract
Abstract Exposure to nickel (Ni) compounds is known to induce human lung malignancies. Research shows that Ni induces lung cancer mainly through epigenetic and metabolic pathways. Polo-like kinase 3 (Plk3) is a multifunctional protein kinase that involves in tumor initiation and progression. Plk3−/− mice tend to develop highly vascularized lung tumors at an advanced age. Reduced expression of Plk3 was reported in human lung cancers. In this study, we examined the effect of Ni on Plk3 expression in A549 lung carcinoma cells. Western blot showed that NiCl2 reduced the Plk3 protein level in a time- and dose-dependent manner. We then treated A549 cells with cycloheximide for various times to examine the effect of NiCl2 on the half-life of Plk3 protein. We observed a shortened half-life of Plk3 in the presence of NiCl2. A reduced level of Plk3 protein was also found in hypoxia-treated A549 cells. In addition, MG132, a specific proteasome inhibitor, could partially reverse the effect of NiCl2 or hypoxia on the Plk3 protein level. Our cell fractionation experiments showed that majority of the endogenous Plk3 protein is located in the cytoplasm where degradation of Plk3 likely occurs. Transfection of A549 cells with FLAG-tagged ubiquitin (FLAG-Ub) followed by treatment with NiCl2 and/or MG132, immunoprecipitation (IP) with an anti-FLAG antibody, and Western blot with an anti-Plk3 antibody showed that Plk3 was poly-ubiquitinated and that the ubiquitination was significantly enhanced by NiCl2 and/or MG132 treatments. The elevated ubiquitination of Plk3 in response to NiCl2 was further confirmed in 293T cells with co-transfection of Plk3 and FLAG-Ub. Furthermore, overexpression of USP28, a deubiquitinase known to be inhibited by Ni or hypoxia, partially restored the protein level of Plk3 suppressed by NiCl2. Moreover, real-time PCR analysis showed that NiCl2 also reduced the Plk3 mRNA level, in a time- and dose-dependent pattern. Taken together, our data show that NiCl2 suppresses Plk3 expressions by lowering the Plk3 mRNA level and promoting proteasome-mediated degradation of the Plk3 protein. Given the potential role of Plk3 as a tumor suppressor in the lung, suppression of Plk3 expression likely contributes to Ni-induced lung carcinogenesis and tumor progression. Citation Format: Cen Li, Soyoung Park, Wei Dai, Dazhong Xu. Suppression of Plk3 expression by nickel may contribute to lung carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3655.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.005 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".