Cbl-Deficient Mice Display Erythropoietin Hypersensitivity and Enhanced Phosphorylation of Protein Kinase B/Akt.
Bibliographic record
Abstract
Abstract Erythropoietin (EPO) is the primary cytokine regulator of erythropoiesis, stimulating growth, preventing apoptosis, and promoting differentiation of red blood cell progenitors. The critical importance of EPO, EPO receptor (EPO-R) and JAK2 to erythropoiesis is demonstrated by the fatal embryonic anemia that develops in EPO, EPO-R or JAK2 knockout mice. Intracellular signal transduction pathways regulating growth, differentiation and cell survival downstream of the EPO-R and JAK2 are well documented. However, activation of the EPO-R is transient and down regulated by several negative regulators including tyrosine phosphatases, inositol phosphatases and ubiquitin ligases. The negative regulator, Cbl, has been implicated as a tumour suppressor in murine sarcoma, B cell leukemia, and erythroleukemia. More recently, Cbl was found in a de novo form of acute myeloid leukemia and has been implicated in the formation of gastric tumours. Cbl is known to bind, ubiquitinate, and downregulate signaling from numerous activated hematopoietic and non-hematopoietic receptors. The discovery that Cbl is a target of EPO-dependent tyrosine phosphorylation, together with the finding that the EPO-R is ubiquitinated in vivo, led us to hypothesize that Cbl deficiency leads to altered murine erythropoiesis. Resting C57Bl/6 Cbl-/- mice display normal hematologic parameters with the exception of an increased platelet count. However, Cbl deficient mice respond to phenylhydrazine-mediated anemia with increased reticulocyte production and hematocrit recovery. The hypersensitivity of Cbl deficient mice to anemia may be explained by a three-fold enhancement of splenic colony forming unit-erythroid (CFU-E) and an overall increase in burst forming unit-erythroid (BFU-E) and CFU-E. Furthermore, the elevated sensitivity of Cbl deficient mice to anemia is echoed by increased EPO-R and protein kinase B (PKB)/Akt phosphorylation in splenic erythroblasts at high levels of EPO stimulation. Erythrocyte differentiation was examined by monitoring the expression of the erythroid markers CD71 (Transferrin Receptor) and Ter119. Cbl deficient mice do not have significantly more proerythroblasts than wild-type mice. Interestingly, Cbl deficient mice show impaired erythroid maturation with a 1.7 fold decrease in orthochromatophilic erythroblast levels, elevated erythroid apoptosis in the bone marrow, and no compensation by splenic erythroblast production. These data (as well as earlier studies from our laboratory with STAT1-/- and SHIP-1-/- mice) illustrate the remarkable ability of the spleen to compensate for alterations in bone marrow erythropoiesis. It also suggests that Cbl regulates pathway(s) associated with regulation of erythroid cell survival through regulation of the PI 3 kinase, PKB/Akt signaling cascade.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.008 | 0.002 |
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".