Abstract LB-124: RHAMM acts near chromosomes to promote mitotic spindle assembly by regulating the location and abundance of TPX2 and the downstream activation of Aurora A.
Notice bibliographique
Résumé
Abstract Enhanced cell proliferation is a hallmark of cancer. Thus, molecular pathways underlying mitosis are important targets for therapy. To form a bipolar mitotic spindle, the dividing cell must assemble microtubules at centrosomes [spindle poles] as well as non-centrosome sites [kinetochores]. The spindle then captures and aligns the duplicated chromosomes. Correct attachment satisfies the spindle assembly checkpoint (SAC) and allows for mitotic progression. Aurora kinase A, when bound by its activator, TPX2, is a key regulator of spindle assembly. Upon activation, the kinase phosphorylates substrates to target them to the centrosomes, and protects them from proteolytic degradation. Since it is necessary for optimal Aurora A function, TPX2 availability is tightly controlled. The receptor for hyaluronan-mediated motility (RHAMM) is a microtubule associated protein that interacts with TPX2 and participates in spindle assembly. However, it is unclear whether or how the RHAMM-TPX2 complex modulates Aurora A activity. We hypothesize that RHAMM interacts with TPX2 to determine TPX2 location and abundance, which facilitates Aurora A activity and spindle assembly. We have followed the location and interactions of RHAMM through mitosis, as well as the consequences for its loss of function. We tracked the location of RHAMM and GFP-RHAMM and found it at the kinetochores. Then, we colocalized RHAMM with key kinetochore proteins, BUBR1 and NDC80, during microtubule nucleation and confirmed physical associations by IP. For insights into the function of RHAMM, we followed mitotic cells in real-time. In HeLa cells treated with siRNA targeting RHAMM, we found a significant increase in aberrant spindle morphology and mitotic failure, and we were able to rescue these phenotypes by reintroducing GFP-RHAMM. We also measured the duration of spindle assembly, chromosome congression and cytokinesis. RHAMM depleted mitotic cells present two distinct phenotypes, and these cells either fail spindle assembly or construct phenotypically “normal” mitotic spindles that do not satisfy the SAC. Thus, the protein's location, interactions, and the consequences of its depletion all point to a critical role at the kinetochore. Previous reports suggest RHAMM participates in spindle assembly by interacting with TPX2, however, the exact mechanism remains unknown. We find that RHAMM depletion decreases TPX2 protein abundance during early mitosis, and impairs TPX2 transit to the spindle poles, which results in reduced Aurora A protein abundance and activity. Together, these results suggest that RHAMM influences Aurora A actions by regulating the stability and location of TPX2. Further insights into RHAMM associated pathways may lead to the discovery of new therapeutic targets and optimize the usage of promising drugs such as Aurora A inhibitors. Citation Format: Helen Chen, Chinten Lim, Chris Maxwell. RHAMM acts near chromosomes to promote mitotic spindle assembly by regulating the location and abundance of TPX2 and the downstream activation of Aurora A. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-124. doi:10.1158/1538-7445.AM2013-LB-124
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 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,005 | 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 ».