Abstract 4023: Novel role of neurofibromin in transport of RNA granules
Bibliographic record
Abstract
Abstract Neurofibromatosis 1 (NF1) is the most common tumor predisposing syndrome in humans, with an incidence of 1:3500 live births. Neurofibromin, encoded by Nf1, acts as a p21-Ras-GAP to directly interact with and inactivate p21-Ras, through its’ GAP Related Domain (GRD). Evidence suggests that non-Ras-GAP functions mediated through interactions with domains outside of the GRD are of importance. By making a number of NF1-GST domain constructs coupled with differential Mass Spec analysis, we identified LRPPRC and Dynein as previously unreported NF1-TBD interacting proteins. LRPPRC was of interest as it is mutated in the Leigh Syndrome French Canadian (LSFC) variant, a cytochrome-oxidase deficiency syndrome, characterized by neurodegeneration, developmental- mental- and growth-retardation, thereby having some similarities with non-tumor manifestations of NF1. We have established that LRPPRC and neurofibromin interact in vitro by immunoprecipitation and reverse bait immunoprecipitation. Use of a novel Proximity Ligation Assay (PLA) was used to further confirm the interaction in situ in cell lines and clinical tissue cryosections. Towards elucidating the functional relevance of the interaction, we have established that the two proteins complex with microtubules and motor proteins, which indicates a role in microtubule-dependant intracellular transport. Since LRPPRC binds with mRNA and is involved in its nucleocytosolic shuttling, we hypothesize that the cargo transported by this complex could be RNA granules. Mass Spec analysis of NF1 immunoprecipitates revealed a number of proteins that are a part of the RNA granule complex which include RNA binding proteins and proteins involved in mRNA translation. By performing RNA Immunoprecipitation (RIP) with NF1 and LRPPRC antibodies, we have demonstrated that the two proteins do complex with 18S and 28S rRNA which is indicative of the presence of intact mRNA. Towards identifying the specific messages transported by the NF1-LRPPRC RNA granule complex we are performing RIP - microarray gene expression profiling (CHIP). The resultant candidate mRNAs will be further investigated to understand the importance of this novel interaction and novel mechanism towards some of the overlap of neurological and developmental manifestations between LSFC and NF1. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4023.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.000 |
| 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".