Eukaryotic Initiation Factor 3F (eIF3F) Regulates the IRES-Mediated Translation of Bcl-xL via Its Interaction with Programmed Cell Death 4 (PDCD4) Protein
Bibliographic record
Abstract
Abstract Programmed cell death 4 (PDCD4) protein is a well-characterized tumor suppressor protein. PDCD4 inhibits mRNA translation by inhibiting the activity of an RNA helicase, eukaryotic initiation factor 4A (eIF4A). We have previously reported that PDCD4 interacts with the internal ribosome entry site (IRES) element that is found within the 5’ untranslated region (UTR) of mRNA encoding B-cell lymphoma extra-large (Bcl-xL) protein. PDCD4’s interaction with the Bcl-xL IRES element inhibits the IRES-mediated translation initiation on Bcl-xL mRNA. However, S6 kinase (S6K)-mediated phosphorylation of PDCD4 activates its degradation by proteasomal degradation pathway and derepress IRES-mediated translation initiation of Bcl-xL mRNA. Interestingly, eIF3F (one of the 13 subunits of eIF3) was reported to recruit S6K to phosphorylate eIF3. Therefore, we were intrigued by the possibility of co-regulation of PDCD4 and eIF3F by S6K and the regulation of IRES-mediated translation initiation by PDCD4-eIF3F. To this end, using co-immunoprecipitation (co-IP), we demonstrated that PDCD4 interacts with several subunits of eIF3. Reciprocal co-IP, endogenous IP, and in vitro pull-down assays demonstrated that eIF3F directly interacts with PDCD4 in an RNA-independent manner. In order to functionally characterize the PDCD4-eIF3F complex, we depleted PDCD4 from the glioblastoma (GBM) cells, which resulted in decreased levels of eIF3F. Also, depletion of eIF3F from GBM cells reduced the levels of PDCD4 protein. However, this was not observed in non-cancer cells. Overexpression of PDCD4 resulted in enhanced levels of eIF3F, and vice versa . We further confirmed that the interaction of eIF3F and PDCD4 proteins prevents each other’s proteasomal degradation. By performing RNA-IP, we showed that PDCD4 and eIF3F interact with Bcl-xL RNA independently. Moreover, our IRES-bi-cistronic reporter assay and polysome profiling experiments demonstrated that eIF3F regulates IRES-mediated translation of Bcl-xL mRNA, likely via its interaction with PDCD4. Significance This study uncovers the fundamental mechanism of the internal ribosome entry site (IRES)- mediated translation regulation of B-cell lymphoma extra-large (Bcl-xL) mRNA by programmed cell death 4 (PDCD4) protein, and the eukaryotic initiation factor 3F (eIF3F). Our results show that PDCD4 and eIF3F interact with each other directly and they also interact with Bcl-xL mRNA independently. We show that PDCD4 works via eIF3F to regulate Bcl-xL levels. We also show that the PDCD4-eIF3F-dependent mechanism of Bcl-xL mRNA translation is implicated in glioblastoma (GBM) cells, including the primary brain tumor stem cells (BTSCs), and would likely affect the GBM pathophysiology.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.001 |
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".