Examination of the mechanisms of PTHRP cytosolic relocation and nuclear import
Bibliographic record
Abstract
Parathyroid hormone-related peptide (PTHrP) is a factor with numerous biological functions elicited either by secreted isoforms activating the cell surface type 1 PTH receptor or by intracrine species mediating actions at the level of the cell nucleus/nucleolus. To gain insight into the mechanism(s) whereby PTHrP, normally a secreted protein, bypasses the secretory pathway and enters the cytosol for subsequent nuclear import, we characterized its nuclear forms. In transfected COS-1 cells, three nuclear PTHrP isoforms were identified, which were larger than the mature protein but smaller than preproPTHrP and comprised both the peptide's amino and carboxyl termini. These also encompassed part of the prepro domain, suggesting that they likely arise from alternate initiation of translation at downstream non-AUG codons. Indeed, PTHrP cDNAs in which either the unique initiator AUG was inactivated or that encompassed an engineered N-linked glycosylation site, were capable of generating nuclear PTHrP isoforms that were inefficiently targeted to the ER, bypassed ER transit, and localized exclusively to the nucleus/nucleolus. Codons involved in the generation of nuclear PTHrP forms were delineated using site-directed mutagenesis analysis of nucleotides within the prepro region. Indirect immunofluorescence, in vitro transcription/translation, and radiosequencing studies of various mutants established that nuclear PTHrP peptides are concurrently translated from internal CUG -32 and -25, and GUG -24 triplets. In addition, we examined PTHrP phosphorylation by cdc2 kinase and its role in nuclear translocation. Bacterial recombinant and in vitro translated PTHrP, and a peptide encompassing a consensus cdc2 kinase target sequence were phosphorylated by purified enzyme. Using mutant forms of PTHrP that could not be phosphorylated by cdc2 kinase at individual target residues or at all putative sites, it was demonstrated that the protein's subcellular distribution was unaltered. Pho
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) | 0.000 | 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 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".