Impaired Transforming Growth Factor-β (TGF-β) Transcriptional Activity and Cell Proliferation Control of a Menin In-frame Deletion Mutant Associated with Multiple Endocrine Neoplasia Type 1 (MEN1)
Bibliographic record
Abstract
Background: Mutations in menin cause multiple endocrine neoplasia type 1 (MEN1).Results: We identified an MEN1 in-frame deletion mutant of menin.Conclusion: The mutant was stable, had selective loss of TGF- signaling and growth inhibition, and identified the menin/ Smad3 interacting region.Significance: The studies provide insights into the pathophysiology of MEN1 and suggest the menin/Smad3 interface as a potential therapeutic target.Multiple endocrine neoplasia type 1 (MEN1) is characterized by tumors of the parathyroid, enteropancreas, and anterior pituitary.The MEN1 gene encodes the tumor suppressor menin of 610 amino acids that has multiple protein partners and activities.The particular pathways that, when lost, lead to tumorigenesis are not known.We demonstrated that members of a three-generation MEN1 kindred are heterozygous for a donor splice site mutation at the beginning of intron 3 (IVS3 ؉ 1G3 A).Lymphoblastoid cells of a mutant gene carrier had, in addition to the wild-type menin transcript, an aberrant transcript resulting from use of a cryptic splice site within exon III that splices to the start of exon IV.The predicted menin ⌬(184 -218) mutant has an in-frame deletion of 35 amino acids but is otherwise of wild-type sequence.The transfected menin ⌬(184 -218) mutant was well expressed and fully able to mediate the normal inhibition of the activity of the transcriptional regulators JunD and NF-B.However, it was defective in mediating TGF--stimulated Smad3 action in promoter-reporter assays in insulinoma cells.Importantly, lymphoblastoid cells from an individual heterozygous for the mutation had reduced TGF--induced (Smad3) transcriptional activity but normal JunD and NF-B function.In addition, the mutant gene carrier lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF- than cells from an unaffected family member.In conclusion, the menin mutant exhibits selective loss of the TGF- signaling pathway and loss of cell proliferation control contributing to the development of MEN1.
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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) | 0.001 | 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 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".