Kaposi sarcoma associated herpesvirus infection of primary human endothelial cells activates the proto-oncogene STAT3
Bibliographic record
Abstract
Kaposi’s sarcoma associated herpesvirus (KSHV) in the etiological agent for 3 AIDS-related cancers: Kaposi’s sarcoma (KS), primary effusion lymphoma, and multicentric Castleman’s disease. The molecular mechanisms used by KSHV to induce cancer are incompletely understood. KS lesions harbor proliferating latently-infected endothelial cells (ECs), large numbers of inflammatory cells, and marked neoangiogenesis. Considered the major driving force in the development of KS, these KSHV-infected ECs elaborate a variety of pro-inflammatory and angiogenic factors that contribute to tumourigenesis. Considerable evidence has accumulated suggesting a critical role for activated signal transducer and activator of transcription-3 (STAT3) in malignant transformation. STAT3 is a latent transcription factor that upon activation, drives the expression of a number of genes involved in cell proliferation, survival, and immune responses. Canonical STAT3 activation occurs via phosphorylation of Y705, dimerization, and nuclear translocation, followed by phosphorylation of S727 for maximal transcriptional activity. Activated STAT3 has been observed in a variety of malignancies and has been shown to induce fibroblast transformation in vitro suggesting that STAT3 is a proto-oncogene. Interestingly, evidence has accumulated suggesting a role for S727 mono-phosphorylated STAT3. Here we show that latent KSHV infection of primary human endothelial cells (ECs) in vitro activates STAT3, and identify a key latency protein, kaposin B, that contributes to this activation. Kaposin B expression in ECs causes STAT3 phosphorylation at S727, in the absence of significant Y705 phosphorylation, and enhanced expression of a subset of STAT3 target genes including CCL5. Recent work shows that the tripartite motif-containing protein 28 (TRIM28, a.k.a. TIF-1β, KAP-1) negatively regulates STAT3 by recruiting transcriptional silencing complexes. The repressive activity of TRIM28 is mediated by post-translational modifications and a key site in the regulation of repressor activity maps to S473. Phosphorylation of this residue disrupts the recruitment of transcriptional silencing complexes effectively deactivating the co-repressive function of TRIM28. Confocal microscopy and western blot analysis demonstrate phosphorylation of TRIM28 at S473 in KSHV latently infected and kaposin B expressing ECs. Taken together, our studies suggest kaposin B may contribute to tumourigenesis via constitutive activation of STAT3.
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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".