Polycomb Group Ring Finger 5 (PCGF5) Is a Notch Transcriptional Target and Regulates Cell Size and Cell Cycle in Hematopoietic Progenitors.
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".