Abstract 5431: Activation of Myocardin Function by an Ubiquitin E3 Ligase, EDD
Bibliographic record
Abstract
Fully differentiated mature smooth muscle cells (SMCs) are characterized by the presence of a unique repertoire of contractile proteins. The expression of these proteins is markedly attenuated during the de-differentiation of smooth muscle that occurs under many pathological conditions. SRF is a transcription factor that plays a central role in the expression of these smooth muscle-specific genes through physical association with various cell-restricted or signal dependent accessory factors. Of the SRF-associated proteins identified, myocardin is the most potent for stimulating expression of smooth muscle-specific genes. Although several proteins have been identified that can modify myocardin function, the mechanism of how myocardin regulation is still poorly understood. To identify additional myocardin associated proteins that are required for myocardin-dependent activation smooth muscle-specific genes we performed a yeast 2-hybrid screen of mouse embryo cDNA library using myocardin as bait. From this screen we identified a HECT domain containing protein EDD as a myocardin binding protein. Previous studies have shown that HECT domain containing proteins are ubiquitin E3 ligases that play an important role in protein degradation. EDD has however, also been shown to regulate transcription independent of its E3 ligase activity. In the current study we demonstrated that the amino-terminal domain of myocardin bound to the HECT domain of EDD. We also show that EDD specifically enhanced trans-activation of smooth muscle-specific promoters by myocardin. Furthermore, EDD significantly augmented myocardin’s ability to induce expression of endogenous SMC marker genes, and these effects of EDD were independent on its E3 ligase function. Conversely, depletion of endogenous EDD in fibroblast cells by RNAi attenuated myocardin-induced smooth muscle-specific gene expression, and EDD knockdown in smooth muscle cells resulted in down-regulation of smooth muscle-specific genes. Ongoing experiments are investigating the mechanism by which EDD activates myocardin function. This study reveals an unexpected role for the ubiquitin E3 ligase EDD as an activator of smooth muscle differentiation through its ability to potentiate myocardin function. This research has received full or partial funding support from the American Heart Association, National Center.
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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) | 0.003 | 0.001 |
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".