Abstract LB-022: The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation
Bibliographic record
Abstract
Abstract The p53 tumor suppressor family is comprised of three members: p53, p63, and p73. These transcription factors can negatively regulate cell proliferation by inducing the expression of proteins related to apoptosis (ex. bax) and cell cycle arrest (ex. p21). Isoforms of the p63 protein can be divided into two major groups, the transcriptionally active TAp63 variants, and the dominant-negative ΔNp63 variants. The TAp63 variants are considered to be tumor suppressor proteins that can cooperate with p53 and p73 to prevent cancer development. Unlike p53, which is frequently mutated in cancer, TAp63 is rarely mutated, and its transcription function is primarily regulated at the protein level. One such method of regulation at this level is proteasome-mediated degradation, initiated by tagging the substrate protein with a poly-ubiquitin chain recognized by the proteasome. This ubiquitination is mediated by E-3 ligases such as Mdm2 and AIP4, two previously characterized regulators of the p53 family. In this study, we report that CHIP, an E-3 ligase involved in protein chaperoning during the heat shock response is a negative regulator of TAp63. The purpose of this study was to characterize CHIP as a TAp63-interacting protein that negatively regulates TAp63 expression and function. Using transient transfection assays, we found that CHIP can bind to, ubiquitinate, and reduce the expression of TAp63 in H1299 lung carcinoma cells. Stably knocking down CHIP expression in these cells using anti-CHIP shRNA restores endogenous p63 expression. This negative regulation of TAp63 by CHIP is associated with a decrease in p21 promoter transcription (measured by a luciferase reporter assay), cell cycle arrest and cellular apoptosis (measured by flow cytometry), and accompanied by an increase in cell survival (measured by colony forming assay) and invasive capacity (measured by a cell scattering assay). An immunoblot analysis of carcinoma cell lines and invasive prostate cancer tissue samples also demonstrates a negative correlation between CHIP and TAp63 expression levels. We conclude that CHIP is a negative regulator of TAp63 expression and function, and, therefore, has an oncogenic role in context with TAp63. Citation Format: Stephen R. Armstrong, Benfan Wang, Yasser Abuetabh, Roger Leng. The E3-ligase CHIP negatively regulates the expression and function of the tumor suppressor TAp63 through ubiquitination and subsequent proteasome-mediated degradation. [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 LB-022.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".