The role of platelet-derived growth factor-BB signaling in glycosaminoglycan formation in fetal lung cells
Bibliographic record
Abstract
Elucidation and genetic determination of the signal transduction pathway(s) that results in platelet-derived growth factor (PDGF-BB)-induced glycosaminoglycan (GAG) synthesis as well as protection from apoptosis were undertaken. Over-expression of a soluble PDGF β-receptor as well as a mutated form of the β-receptor, unable to bind PI-3K, diminished GAG synthesis in fetal lung fibroblasts subsequent to PDGF-BB stimulation. Treatment with the PI-3K inhibitor, wortmannin or expression of dominant-negative PI-3K abrogated Akt activity and GAG synthesis. Furthermore, expression of dominant-negative Akt (Akt-AAA) abrogated endogenous Akt activity, Rab3D phosphorylation and GAG synthesis whereas expression of constituitively activated Akt (Akt-DD) stimulated Rab3D phosphorylation and GAG synthesis in the absence of PDGF-BB. Over-expression of wild-type PTEN inhibited Akt activity and concomitantly attenuated GAG synthesis in fibroblasts stimulated with PDGF-BB. These data suggest that Akt is an integral protein involved in PDGF-BB-mediated GAG regulation in fetal lung fibroblasts. As the Akt pathway has been implicated in cell survival mechanisms, it was investigated whether the pathway regulating GAG secretion was anti-apoptotic. Transfection of constituitively-active Akt into fetal lung fibroblasts lead to an increase in GAG secretion, without PDGF-BB stimulation, that safeguarded the cells from apoptosis. Separate cultures of lung fibroblasts were treated with xyloside, a proteoglycan substitute, or with topologically applied GAGs. Application of xyloside or the sulfated GAGs, chondroitin sulfate or heparan sulfate, resulted in an increase in GAG secretion, diminished apoptosis as well as an increase in BAD phosphorylation and diminished caspase cleavage, all of which are indicative of an anti-apoptotic response. PDGF-BB also increased p42 mitogen-activated protein kinase (MAPK), although it was determined not to be a component of the GAG pathway. However, MAPK is an enzyme that, together with Akt, phosphorylates and sequesters BAD. Overexpression of a dominant-negative PDGFβ-receptor, lacking the cytoplasmic signaling domain, or a dominant-negative PDGFβ-receptor, with cytoplasmic tyrosines mutated to phenylalanine, abrogated p42MAPK activity suggestive that PDGF-BB mediated activation of p42MAPK requires the PDGFβ-receptor but is independent of its tyrosine phosphorylation. The data contained herein are demonstrative of a concerted and pleiotropic response initiated by the GAG signal transduction pathway as a means to ensure appropriate fetal lung development.
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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".