A276 INVESTIGATING THE ROLE OF TTC7A THROUGH ITS INTERACTION WITH UBR5 TO MAINTAIN CELL SURVIVAL
Notice bibliographique
Résumé
Patients with mutations in Tetratricopeptide Repeat Domain 7A (TTC7A) results in a severe and untreatable form of inflammatory bowel disease with the majority dying before 2 years of age. Pathological features of these patients include intestinal apoptosis and disrupted apicobasal polarity. Since the molecular function of TTC7A is still poorly understood, we recently carried out a screen identifying potential TTC7A binding partners in an attempt to reveal its pathway of action. TTC7A is part of an evolutionarily conserved pathway and acts as a scaffolding protein recruiting phosphatidylinositol 4-kinase, PI4KIIIα, to the plasma membrane where it also binds to EFR3B. This conserved pathway helps PI4KIIIα phosphorylate phosphatidylinositol (PI) to PI-4-phosphate (PI4P) which has been implicated in cell survival and the maintenance of cell polarity. In addition, the E3 ubiquitin ligase, UBR5, was identified as a potential TTC7A binding protein and may play a role in stabilizing TTC7A protein levels. Furthermore, UBR5 is suggested to be a colorectal oncogene because it interacts with β-catenin to upregulate canonical Wnt signaling. UBR5 has also been implicated as a tumour suppressor gene and in regulating apoptosis. To understand the role of TTC7A and UBR5 in cell survival. We hypothesize that UBR5 is involved and required in the PI4KIIIα-TTC7A-EFR3B pathway to maintain cell survival. Vector constructs were created harbouring patient derived TTC7A mutations (E71K, Q526X, A832T) and expressed in HEK 293T cells. TTC7A immunoprecipitates (IP) were analyzed by tandem mass spectrometry identifying various binding proteins. To validate these potential TTC7A interacting proteins, co-IP was performed by co-transfecting cells with appropriate expression plasmids and then lysing the cells after 24hrs. Protein of interest was IP using the target antibody. Whole cell lysate and co-IP samples were subject to Western blot analysis. Preliminary results show an interaction between the UBR5 and TTC7A along with the patient derived TTC7A variants. They also show the presence of PI4KIIIα in the UBR5/TTC7A complex. Furthermore, they suggest that β-catenin only interacts with UBR5 in the presence of TTC7A. The presence of PI4KIIIα in the UBR5/TTC7A complex implies that UBR5 is part of the conserved pathway to maintain cell survival through the downstream PI4P levels. Western blot analysis shows that UBR5 interacts most strongly with the TTC7A Q526X. A possible explanation is that the truncated TTC7A Q526X is ubiquitinated by UBR5 for proteasomal degradation, resulting in decreased PI4P levels. Also, the study suggests that TTC7A recruits β-catenin for ubiquitination by UBR5. Together, the research supports the notion that TTC7A is involved in multiple pathways with UBR5 to maintain cell survival or in causing colorectal cancer. None
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».