TNFAIP8: A new effector for Galpha(i) coupling to reduce cell death and induce cell transformation
Bibliographic record
Abstract
Galpha(i)-coupled receptors comprise a diverse family of receptors that induce transformation by largely unknown mechanisms. We previously found that the Galpha(i)-coupled dopamine-D2short (D2S) receptor transforms Balb-D2S cells via Gαi3. To identify new Gαi effectors, a yeast two-hybrid screen was done using constitutively active Gαi3-Q204L as bait, and tumor necrosis factor-alpha (TNFα)-induced protein 8 (TNFAIP8, SCC-S2/NDED/GG2-1) was identified. In contrast, TNFAIP8-related TIPE1 and TIPE2 showed a very weak interaction with Gαi3. In yeast mating, in vitro pull-down, co-immunoprecipitation and bioluminescence resonance energy transfer (BRET) assays, TNFAIP8 preferentially interacted with activated Gαi proteins, consistent with direct Gαi-TNFAIP8 coupling. Over-expression or depletion of TNFAIP8 using antisense constructs in Balb-D2S cells did not affect D2S-induced signaling to Gαi-dependent inhibition of cAMP. In contrast, antisense depletion of TNFAIP8 completely inhibited spontaneous and D2S-induced foci formation, consistent with a role for TNFAIP8 in Gαi-dependent transformation. To address possible mechanisms, the effect of D2S signaling via TNFAIP8 on TNFα action was examined. D2S receptor activation inhibited TNFα-induced cell death in Balb-D2S cells, but not in cells depleted of TNFAIP8. However, depletion of TNFAIP8 did not prevent D2S-induced inhibition of TNFα-mediated caspase activation, suggesting that D2S/TNFAIP8-induced protection from TNFα-induced cell death is caspase-independent. The data suggest that Gαi-TNFAIP8-mediated rescue of pre-oncogenic cells enhances progression to oncogenic transformation, providing a selective target to inhibit cellular transformation.
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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 | 0.000 | 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) | 0.000 | 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".