Hypoxia-induced transcriptional repression of the melanoma-associated oncogene <i>MITF</i>
Bibliographic record
Abstract
Microphthalmia-associated transcription factor (MITF) regulates normal melanocyte development and is also a lineage-selective oncogene implicated in melanoma and clear-cell sarcoma (i.e., melanoma of soft parts). We have observed that MITF expression is potently reduced under hypoxic conditions in primary melanocytes and melanoma and clear cell sarcoma cells through hypoxia inducible factor 1 (HIF1)-mediated induction of the transcriptional repressor differentially expressed in chondrocytes protein 1 (DEC1) (BHLHE40), which subsequently binds and suppresses the promoter of M-MITF (melanocyte-restricted MITF isoform). Correspondingly, hypoxic conditions or HIF1α stabilization achieved by using small-molecule prolyl-hydroxylase inhibitors reduced M-MITF expression, leading to melanoma cell growth arrest that was rescued by ectopic expression of M-MITF in vitro. Prolyl hydroxylase inhibition also potently suppressed melanoma growth in a mouse xenograft model. These studies illuminate a physiologic hypoxia response in pigment cells leading to M-MITF suppression, one that suggests a potential survival advantage mechanism for MITF amplification in metastatic melanoma and offers a small-molecule strategy for suppression of the MITF oncogene in vivo.
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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".