Abstract LB-046: Mechanism and consequences of HDAC6 regulation by RanBPM
Bibliographic record
Abstract
Abstract Ran-binding protein M (RanBPM) has been shown to interact with numerous proteins, implicating it in a variety of cellular processes including cell adhesion, migration, microtubule dynamics, and gene transcription. Work in our laboratory previously identified RanBPM as an activator of apoptosis induced by DNA damage. Our studies have also suggested a tumour suppressor role for RanBPM, as its downregulation not only disrupted apoptotic activation, but lead to loss of growth factor dependence and increased rates of cell migration. Here we show that RanBPM downregulation promotes tumour formation in orthotopic and metastasis mouse models, further suggesting a tumour-suppressive function for RanBPM. Recently, we characterized an interaction between RanBPM and Histone Deacetylase 6 (HDAC6). HDAC6 is a cytoplasmic deacetylase with an important role in cell migration. Its substrates include α-tubulin, cortactin and Hsp90. Increased HDAC6 expression and/or activity has been demonstrated to promote cell migration and tissue invasiveness. HDAC6 has also been shown to be required for oncogenic transformation and tumour formation. Upregulated HDAC6 has been observed in a number of different cancers and recently, specific HDAC6 inhibitors have been found to inhibit cell growth and prevent tumour formation in mouse models. We previously identified that the interaction between RanBPM and HDAC6 mediates the inhibition of HDAC6. Here we demonstrate that the LisH domain of RanBPM specifically, is responsible for the association with HDAC6. RanBPM also interacts with α-tubulin at microtubules and this localization is dependent on HDAC6, whereas HDAC6 localization at microtubules is independent of RanBPM. RanBPM has been identified to be part of a large protein complex, termed the CTLH complex. Components of the complex are conserved from the homologous yeast complex, the Gid complex, which functions as an E3 ubiquitin ligase complex. Here we evaluate HDAC6 regulation by the CTLH complex and asses co-localization of the CTLH complex with microtubules, specifically α-tubulin. Overall, our results suggest that the tumour suppressor functions of RanBPM could stem, at least in part from an inhibition of the oncogenic activities of HDAC6. Citation Format: Louisa Salemi, Xu Wang, David Hess, Caroline Schild-Poulter. Mechanism and consequences of HDAC6 regulation by RanBPM. [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-046.
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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 | 0.001 |
| 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) | 0.003 | 0.002 |
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".