Molecular interactions between insulin-like growth factor signal transduction and retinoids in breast cancer cells
Notice bibliographique
Résumé
Numerous groups, including ours, have found that retinoids potently inhibit the growth of breast cancer cells, but the mechanisms by which growth regulation is achieved remains unclear. Although several of the effects of retinoids in breast cancer have been linked to the insulin-like growth factor (IGF) system, their effects on key signaling molecules in the IGF type-I receptor (IGF-IR) pathway have not been well characterized. This thesis project examined the hypothesis that retinoids mediate their growth inhibitory effects by targeting specific members of the IGF-IR signal transduction pathway. Although we did not observe regulation of IGF-IR itself, we found that all-trans retinoic acid (RA)-mediated growth inhibition is associated with a selective reduction in insulin receptor substrate 1 (IRS-1) protein and activity levels. We also present evidence that decreasing IRS-1 levels results in the selective down-regulation of the PI 3-kinase/AKT pathway in RA-treated MCF-7 cells. The relevance of IRS-1 regulation to the growth inhibitory action of RA is supported by the results showing that forced expression of IRS-1 abrogates the ability of RA to significantly inhibit MCF-7 cell growth. Several studies have highlighted the importance of IRS-1 in breast cancer pathogenesis. High levels of IRS-1 in human breast tumors correlate with increased disease recurrence and constitutive IRS-1 signaling exists in breast tumors. This suggests that we may develop molecular strategies targeting IRS-1 by understanding the mechanisms controlling its expression and turnover. Since RA decreased IRS-1 protein levels without altering mRNA levels, we examined the hypothesis that RA-mediated regulation of IRS-1 levels was at the posttranslational level. Two proteasome inhibitors rescue the RA-mediated degradation of IRS-1, and RA increases the ubiquitination of IRS-1. We also found that RA increases the serine phosphorylation of IRS-1 and show that this occurs in a protein kinase C (PKC)-dependant manner, since PKC inhibitors block the RA-induced degradation and serine phosphorylation of IRS-1. We further demonstrate that RA activates PKC-delta in the sensitive, but not in the resistant cells, with a time course that is consistent with the RA-induced decrease of IRS-1. The involvement of PKC in the RA-mediated regulation of IRS-1 is supported by additional data showing that: (1) RA-activated PKC-delta phosphorylates IRS-1 in vitro, (2) PKC-delta and IRS-1 interact in RA-treated cells, and (3) mutation of three PKC-delta serine sites in IRS-1 to alanines results in no RA-induced in vitro phosphorylation of IRS-1. Having identified IRS-1 as a novel target of RA and showing that RA regulates this protein via a mechanism involving the ubiquitin-proteasome pathway has contributed to an enhanced understanding of the effect of retinoids in human breast cancer cells.
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 | 0,001 | 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 | 0,002 |
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 ».