Potentiation of ryanodine receptor–mediated calcium release by MAPK is responsible for epidermal transformation and carcinogenesis
Bibliographic record
Abstract
Epidermal growth factor (EGF) induces anchorage-independent growth in promotion-sensitive (P + ) mouse epidermal cell model JB6 primarily through activation of the MAPK/ERK signaling pathway. The β-blocker carvedilol inhibits EGF-promoted JB6 transformation, but the underlying mechanism is unknown. Since carvedilol suppresses overactivated ryanodine receptors (RyRs) independently of its adrenergic blocking effects, we hypothesized that EGF-promoted transformation requires RyR-mediated calcium (Ca 2+ ) release and that carvedilol inhibits transformation via targeting RyRs. All RyR subtypes were present in epidermis and strongly upregulated by ultraviolet (UV) radiation, as demonstrated in an RyR2-tdTomato reporter mouse model. In vitro, EGF induced ERK phosphorylation and RyR2 upregulation and increased RyR agonist 4-chloro-m-cresol (4-CMC)-evoked Ca 2+ release, which is inhibitable by structurally divergent RyR stabilizers and inhibitors of MAPK and PLC, but not by most β-blockers. Expression of constitutively active K-RAS and MEK-1 or UV also potentiated 4-CMC-evoked Ca 2+ release. RyR agonists and the Ca 2+ ionophore ionomycin promoted JB6 transformation while RyR stabilizers, the intracellular Ca 2+ chelator BAPTA/AM, and inhibitors of MAPK and PLC blocked transformation. The RyR shRNAs abolished the transformation-inhibitory effect of carvedilol. The IC 50 values of five carvedilol derivatives for suppressing RyR-mediated Ca 2+ release positively correlated with the IC 50 values for transformation inhibition. In vivo, UV-induced DNA damage and skin inflammation were enhanced by topical 4-CMC treatment but attenuated in the RyR2-E4872Q knock-in mice in which RyR2 activity is reduced. Human skin tissue microarray analysis confirmed spatial colocalization of phospho-ERK and RyR2 in the same tumor areas. Thus, potentiation of RyR-mediated Ca 2+ release by MAPK is an important pathway leading to carcinogenesis.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 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 teacher head, 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".