STAT1 Represses <i>Skp2</i> Gene Transcription to Promote p27Kip1 Stabilization in Ras-Transformed Cells
Bibliographic record
Abstract
The S-phase kinase-associated protein 2 (Skp2) is an F-box protein that serves as a subunit of the Skp1-Cullin-F-box ubiquitin protein ligase complex. Skp2 is overexpressed in many tumors and promotes tumor formation through its ability to induce the degradation of proteins with antiproliferative and tumor-suppressor functions, such as p27(Kip1). The signal transducer and activator of transcription 1 (STAT1) is a key regulator of the immune system through its capacity to act downstream of interferons. STAT1 exhibits tumor-suppressor properties by inhibiting oncogenic pathways and promoting tumor immunosurveillance. Previous work established the antitumor function of STAT1 in Ras-transformed cells through the induction of p27(Kip1) at the transcriptional level. Herein, we unveil a novel pathway used by STAT1 to upregulate p27(Kip1). Specifically, we show that STAT1 impedes Skp2 gene transcription by binding to Skp2 promoter DNA in vitro and in vivo. Decreased Skp2 expression by STAT1 is accompanied by the increased stability of p27(Kip1) in Ras-transformed cells. We further show that impaired expression of STAT1 in human colon cancer cells containing an activated form of K-Ras is associated with the upregulation of Skp2 and downregulation of p27(Kip1). Our study identifies Skp2 as a new target gene of STAT1 in Ras-transformed cells with profound implications in cell transformation and tumorigenesis.
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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 | 0.001 |
| 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 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".