Lysophosphatidic acid-induced transactivation of the EGF receptor regulates connexin43-mediated gap junctional communication in ovarian surface epithelial cells.
Notice bibliographique
Résumé
174 Lysophosphatidic acid (LPA) is released by activated platelets and induces disruption of connexin43 (Cx43)-mediated cell-to-cell communication and enhanced cell proliferation in wound repair. The identification of LPA-activated mediators that regulate the growth-suppressive function of the Cx43 gap junction protein in normal ovarian cells may provide some insight into the development of ovarian cancer. These studies measured gap junctional communication (GJC) in rat ovarian surface epithelial (ROSE) cells by microinjecting a fluorescent dye into single cells and counting the neighboring cells that became fluorescent by dye transfer. Changes in Cx43 phosphorylation were detected by migration differences on SDS-PAGE and activation of protein kinases was demonstrated by Western blotting with phospho-specific antibodies or by immune complex activity assays. LPA induced a dose- and time-dependent fall in GJC in ROSE cells. Pre-treatment with pertussis toxin or a MEK inhibitor (PD98059) blocked the fall in GJC and the increase in Cx43 phosphorylation, supporting a role for a Gi G protein-coupled receptor (GPCR) and Erk kinases in these effects. Pretreatment with the Src family kinase inhibitor PP2 attenuated the fall in GJC and the increased Cx43 phosphorylation. Gi-GPCRs induce c-Src and Erk activation through transactivation of a receptor tyrosine kinase. We pretreated ROSE cells with an EGF receptor (EGFR) inhibitor (PD153035) to examine the role for the EGFR in LPA-induced signaling. Inhibiting the EGFR blocked LPA-induced auto-phosphorylation of the receptor, reduced the extent of Cx43 phosphorylation and prevented the fall in GJC. A recent study by Cameron et al. (JBC 2003) suggested that Erk5 is more important than Erk1/2 in the regulation of GJC in EGF-treated cells. We found that pre-treating ROSE cells with pertussis toxin, MEK inhibitor, PP2 or the EGFR inhibitor prevented the downstream activation of Erk5 in LPA-treated cells. In cells treated with the EGFR inhibitor and then with LPA, Erk1/2 was activated but GJC did not fall. These studies demonstrated that LPA induced Cx43 phosphorylation and disruption of GJC though a Gi-GPCR-dependent signaling pathway that initiated transactivation of the EGFR and activated an Src family kinase and Erk kinases. Importantly, transactivation of the EGFR was required for Erk5 activation and Erk5 was key for the fall in GJC. Since LPA disrupts Cx43-mediated GJC and the down regulation of Cx43 enhances cell proliferation, it is plausible that deregulation of LPA-activated signaling may down regulate the growth-suppressive function of Cx43 in normal ovarian surface epithelial cells and allow proliferation of abnormal cells that arise during the proliferative cycles of wound repair associated with ovulation and thus contribute to the development of ovarian cancer.
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) | 0,001 | 0,000 |
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 ».