P53-dependent and independent mechanisms by which the p53-related protein, ANp73, promotes neuronal survival
Bibliographic record
Abstract
The survival of neurons during nervous system development depends on the interaction of neurotrophins with cell surface receptors, of which the Trk tyrosine kinase family mediates survival and the p75 neurotrophin receptor (p75NTR) mediates apoptosis. Within the cell, these receptors generate functionally antagonistic signal transduction cascades, and the relationship between Trk and p75NTR signaling determines whether a neuron will ultimately survive or die. Downstream of these receptors, the p53 family, which includes p53, p63, and p73, has been shown to be critical mediators of neuronal survival. Like Trk and p75NTR, pro- and anti-apoptotic p53 family members are functionally antagonistic. The p53 tumour suppressor protein is essential for mediating neuronal apoptosis during development. In contrast, the related protein p73, expressed in neurons as an N-terminal-truncated, anti-apoptotic isoform (DeltaNp73), is essential for neuronal survival. The mechanisms by which DeltaNp73 promotes neuronal survival are the subject of this thesis. In the first part of this thesis, we showed that DeltaNp73 promotes sympathetic neuron survival through p53-dependent and independent mechanisms. Our genetic data demonstrated that loss of p53 partially rescued the sympathetic neuron loss seen in p73-/- mice. We confirmed this biochemically by showing that DeltaNp73 acts at multiple levels of the neuronal apoptotic pathway both upstream and downstream of p53. DeltaNp73 inhibited p53-dependent processes such as Apaf-1 and p21 induction, caspase-3 cleavage, and mitochondrial cytochrome c release. DeltaNp73 also inhibited p53-independent induction of Bim and JNK, the latter possibly through an interaction with JNK. We also found a role for p73 in regulating cell size, through mechanisms that do not involve its interactions with p53. In the second part of this thesis, we investigated DeltaNp73's actions on the JNK pathway, which is activated very early in apoptosis, and found that DeltaNp73 acted at or above the level of the JNK kinase MKK4. We also found evidence that the PI3-kinase/Akt survival pathway, a major Trk effector, was involved in regulation of DeltaNp73 levels. Together, these studies suggested that DeltaNp73, through its regulation by the PI3-kinase/Akt survival pathway, acts at multiple levels of the neuronal apoptotic pathway to inhibit apoptosis.
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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 | 0.001 |
| 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".