IKKβ Is Required for Bcl-2-mediated NF-κB Activation in Ventricular Myocytes
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Bibliographic record
Abstract
The transcription factor nuclear factor kappa B (NF-kappa B) is regulated by cytoplasmic inhibitor I kappa B alpha. An integral step in the activation of NF-kappa B involves the phosphorylation and degradation of I kappa B alpha. We have previously reported that I kappa B alpha activity is diminished in ventricular myocytes expressing Bcl-2 (de Moissac, D., Zheng, H., and Kirshenbaum, L. A. (1999) J. Biol. Chem. 274, 29505-29509). The underlying mechanism by which Bcl-2 activates NF-kappa B is undefined. In view of growing evidence that the I kappa B kinases (IKKs), notably IKK beta, are involved in signal induced phosphorylation of I kappa B alpha, we ascertained whether IKK beta is necessary and sufficient for Bcl-2 mediated NF-kappa B activation. Here we demonstrate that expression of Bcl-2 in ventricular myocytes resulted in an increase in NF-kappa B-dependent DNA binding, NF-kappa B gene transcription and reduced I kappa B alpha levels. An increase in the IKK beta kinase activity was observed in cells expressing full-length Bcl-2 but not in cells expressing the BH4 deletion mutant of Bcl-2 (Delta BH4; residues 10-30). Catalytically inactive mutants of IKK beta, but not IKK alpha, suppressed Bcl-2-mediated I kappa B alpha phosphorylation and NF-kappa B activation. Transfection of human embryonic 293 cells with a kinase-defective Raf-1 or a kinase-defective mitogen-activated protein kinase/extracellular signal-regulated kinase kinase-1 (MEKK-1) suppressed Bcl-2-mediated IKK beta activity and NF-kappa B activation. Further, Bcl-2-mediated NF-kappa B activity was impaired in nullizygous mouse embryonic fibroblasts deficient for IKK beta. In this report, we provide the first direct evidence that Bcl-2 activates NF-kappa B by a signaling mechanism that involves Raf-1/MEKK-1 mediated activation of IKK beta.
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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 | 0.001 |
| 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 it