Polycomb Group Ring Finger 5 (PCGF5) Is a Notch Transcriptional Target and Regulates Cell Size and Cell Cycle in Hematopoietic Progenitors.
Notice bibliographique
Résumé
Abstract The highly conserved Notch gene is activated by mutation in more than half of human T cell acute lymphoblastic leukemia (T-ALL) cases. The Notch protein is a transmembrane receptor which, upon binding of its ligand, is cleaved in a series of proteolytic steps releasing the intracellular portion (ICN) to translocate to the nucleus where it acts as a transcriptional activator for target genes such as HES1, Deltex, preTalpha, and c-Myc. To better understand the mechanism by which Notch causes leukemogenesis, microarray gene expression profiling experiments where conducted on five human Notch signaling-dependent T-ALL cell lines which where either mock-treated or treated with a gamma-secretase inhibitor (GSI) to prevent the release of Notch from the membrane. The Polycomb Group gene PCGF5 was identified as one of the genes most strongly downregulated upon Notch inhibition. This regulation was subsequently confirmed by quantitative RT-PCR in both human and mouse leukemia cell lines. Our interest in this gene was encouraged by its homology to the well-known oncogene Bmi-1, which acts to modify chromatin and silence expression of several genes including the cyclin-dependent kinase inhibitors p16 and p19ARF within the CDKN2a locus. Interestingly, we found that inhibition of Notch signaling by GSI treatment in both human and mouse leukemia cells resulted in an increase of both p16 and p19ARF at the mRNA and protein levels. This suggested that Notch may be responsible for maintaining expression of a transcriptional repressor that suppresses p16 and p19ARF. We hypothesize that PCGF5 may be acting in a manner analogous to Bmi-1 in this cellular context and thus mediating p16/p19ARF repression. Studies to test this hypothesis are currently in progress. To further investigate the role of PCGF5 in hematopoiesis, mouse bone marrow progenitors were transduced with retrovirus to express PCGF5 constitutively and transplanted into lethally irradiated recipients. Our results show long term reconstitution by PCGF5-expressing cells with as yet no evidence of PCGF5-induced hematopoeitic malignancy in a small cohort up to 6 months post-transplant. However, we did observe cells expressing high levels of PCGF5 to be skewed toward myeloid lineages, while mid-level expressing cells develop efficiently into lymphocytes. We detected no defects in B cell maturation; however, PCGF5-expressing T cell numbers were significantly lower than controls in the peripheral blood and spleen of recipient animals. Consistent with this observation, fetal thymic organ culture of PCGF5-transduced fetal liver hematopoietic progenitors showed accumulation in the early double negative thymocyte stages. Additionally, we found PCGF5-expressing B and T lymphocytes to be larger than control cells, and preliminary data suggests these cells may be arrested in G2/M phase of the cell cycle. Biochemical studies are also in progress to assess participation of PCGF5 in the Polycomb Repressive Complex PRC-1 and its effect on chromatin structure. In sum, these preliminary data suggest enforced PCGF5 expression, though not oncogenic, alters normal lymphoid/myeloid fate selection by hematopoietic progenitors and may affect lymphoid cell size by altering cell cycle progression.
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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 ».