Survivin Modulates Gene Expression That Connects through An Extensive Functional Signaling Network and Regulates Proliferation of Hematopoietic Stem Cells through Evi-1
Bibliographic record
Abstract
Abstract Abstract 87 Survivin is a member of the inhibitor of apoptosis protein (IAP) family that antagonizes caspases and has been implicated in regulation of apoptosis, cell division and cell cycle both in cancer cells and normal tissues. Survivin is essential for activation of Aurora kinase that phosphorylates Histone H3, an event required for transcriptional regulation and cytokinesis. Although there is no evidence that Survivin directly regulates gene transcription, Bir1, a C. elegans homologue of Survivin, regulates transcription, most likely through Histone phosphorylation by Aurora kinase. We previously showed that Survivin is expressed and growth factor regulated in human CD34+ cells (Fukuda & Pelus. Blood 2001 & 2002). Antagonizing Survivin impairs production of mouse bone marrow hematopoietic progenitor cells in vitro (Fukuda et al. Blood 2004) and conditional Survivin gene deletion in vivo in mice leads to bone marrow ablation as a result from loss of hematopoietic stem and progenitor cells (Leung et al. JEM 2007). However, little is known about signaling pathways downstream of Survivin in hematopoietic stem cells (HSC). Herein, we investigated the mechanism of action of Survivin by creating Survivin gene signature network following gene deletion in HSC and by functional rescue on impaired HSC activity induced by Survivin deletion. Survivin deletion in Tamoxifen-Cre Survivinflox/flox mice led to significant changes in 2,228 mRNA in marrow CD34neg, c-kit+, Sca-1+, lineage− cells. Molecular network of the genes affected by Survivin deletion in HSC were created using DAVID (Huang et al. Nature Protocol 2009) and Cytoscape (Cline et al. Nature Protocol 2007). Among the signaling pathways defined by KEGG (www.kegg.org), phosphatidylinositol signaling pathway was most significantly affected in HSC by Survivin gene deletion (P<0.05). In addition, at least 56 genes regulated by Survivin were connected through an extensive network structured by 183 genes surrounding the phosphatidylinositol signaling pathway. These include Stathmin1, p38, NFkB, Jun D and Evi-1, a transcriptional factor that regulates HSC proliferation and prevents stress-induced cell death. Furthermore, knocking down Survivin induced coincident repression of 43 HSC related genes such as Gata2, Pbx1 and Sal2 in addition to Evi-1. This is consistent with down-regulation of Gata2, Pbx1 and Sal2 by Evi-1 ablation in HSC in vivo (Goyama et al. 2008) and suggests that Evi-1 may function downstream of Survivin to maintain HSC function. To test this hypothesis, marrow cells from conditional Survivin−/− mice were transduced with vector or Evi-1 and transplanted into lethally irradiated normal recipients. Subsequent Survivin deletion in vivo significantly impaired hematopoietic recovery (53.0±4.4% vs 1.6±0.3% donor chimerism in Survivin+/+ and Survivin−/− cells, respectively, P<0.01), whereas Survivin−/− marrow cells over-expressing Evi-1 showed a marginal but significant increase in hematopoietic recovery at 6 months post transplantation (7.9±0.7% donor chimerism, P<0.01 compared to control vector in Survivin−/−). Gata2 over-expression did not affect hematopoietic recovery (0.6±0.1% donor chimerism). None of the mice transplanted with cells harboring ectopic Evi-1 developed leukemia after 12 months, making it unlikely that recovery of donor chimerism is a consequence of clonal expansion of transduced cells by Evi-1. These results suggest that Evi-1 lies down stream of Survivin in HSC and that repression of Evi-1 expression is a functional consequence of Survivin ablation rather than an indirect effect resulting from apoptosis and/or cell cycle alteration of HSC induced by Survivin deletion. Our data indicate that Survivin regulates HSC proliferation at least through Evi-1. Alteration of genes with multiple cellular functions as a consequence of Survivin deletion and the presence of a functional network downstream of Survivin suggest that Survivin regulates multiple effector pathways in HSC, independent of its activity as a caspase inhibitor. Disclosures: No relevant conflicts of interest to declare.
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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) | 0.002 | 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".