CXCR4 Is a PAX Family Transcription Factor Regulated Gene.
Notice bibliographique
Résumé
Abstract CXCR4 is a G protein-coupled receptor expressed on versatile tissue/organ specific stem cells that binds the α-chemokine SDF-1, and the PAX gene family (PAX1 – 9) encodes transcription factors that have been implicated in organogenesis and stem cell development. It has been demonstrated that the SDF-1-CXCR4 axis regulates trafficking of several types of normal early stem/progenitor cells and malignant tumor cells that derive from them. Recently our group focused on the role of CXCR4 in regulating the motility of skeletal muscle stem/progenitors and reported that it is expressed on normal skeletal muscle satellite stem cells (Stem Cells2003; 21: 363.), and is highly up-regulated on rhabdomyosarcomas (RMS) (Blood2002; 100: 2597) originating from transformed muscle satellite cells. We observed that the expression of CXCR4 correlated with the presence of PAX3 and PAX7 transcription factors (muscle satellite stem cells) and was up-regulated in RMS cells that express the more active version of PAX genes, PAX3-FKHR and PAX7-FKHR fusion proteins. Based on this we hypothesized that PAX genes regulate CXCR4 expression in normal muscle satellite stem cells and their more active fusion-gene counterparts are responsible for up-regulation of CXCR4 in RMS. To better address this issue, we first compared CXCR4 expression by real-time RT-PCR and FACS in several human RMS cells lines and found that expression of CXCR4 correlated with the more metastatic, alveolar subtype of RMS and a better responsiveness to SDF-1. Second, sequence analysis of the CXCR4 promoter revealed several putative PAX gene binding sites (ATTA and GTNNN motifs) at −658–672, −696–709, −737–758, −809–821, −1580–1610, −1693–1697, −1853–1857, −1865–1879, −1937–1946, −2195–2199 and −2297–2302 bp of the reported CXCR4 promoter sequence. Third, to evaluate whether PAX regulates the expression of CXCR4, a 2335 bp upstream fragment of the human CXCR4 promoter gene or its shorter fragments (1819 bp, 1547 bp, 850 bp, 528 bp and 106 bp) were subcloned into a CAT basic reporter gene plasmid and assayed in cells expressing or not expressing the PAX3-FKHR fusion gene. We observed that the CAT activity of all promoter fragments except the 1547 bp fragment was significantly enhanced in cells transduced with the PAX3-FKHR expression vector, what suggests the presence of a negative regulatory element in addition to several positive regulatory PAX binding domains. No promoter activity was observed with the smallest 106 bp fragment. Finally, chromatin immunoprecipitation (ChIP) assay revealed that the PAX3-FKHR protein binds to the CXCR4 promoter. Thus, we provide evidence that expression of CXCR4 is regulated by PAX transcription regulatory factors. Furthermore, we postulate that various PAX proteins that bind to similar DNA consensus sequences may regulate CXCR4 expression in various early normal stem/progenitor cells in a tissue-specific manner (e.g., PAX 1 in osteoblastic progenitors, PAX 3 in neural-crest and skeletal muscle progenitors, PAX 5 in B lymphocytes, PAX 6 in endocrine pancreatic progenitors, PAX 7 in skeletal muscle satellite cells, etc.), what is crucial for proper trafficking of these cells during organogenesis. Furthermore, the potential deregulation of PAX genes in tumor cells leads to overexpression of CXCR4, enhanced responsiveness to SDF-1 and metastasis.
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) | 0,010 | 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 ».