Cytoplasmic Accumulation of Incompletely Glycosylated SHBG Enhances Androgen Action in Proximal Tubule Epithelial Cells
Bibliographic record
Abstract
Human sex hormone-binding globulin (SHBG) accumulates within the cytoplasm of epithelial cells lining the proximal convoluted tubules of mice expressing human SHBG transgenes. The main ligands of SHBG, testosterone and its metabolite, 5α-dihydrotestosterone (DHT), alter expression of androgen-responsive genes in the kidney. To determine how intracellular SHBG might influence androgen action, we used a mouse proximal convoluted tubule (PCT) cell line with characteristics of S1/S2 epithelial cells in which human SHBG accumulates. Western blotting revealed that SHBG extracted from PCT cells expressing a human SHBG cDNA (PCT-SHBG) is 5-8 kDa smaller than the SHBG secreted by these cells, due to incomplete N-glycosylation and absence of O-linked oligosaccharides. PCT-SHBG cells sequester [(3)H]DHT more effectively from culture medium than parental PCT cells, and the presence of SHBG accentuates androgen-dependent activation of a luciferase reporter gene, as well as the endogenous kidney androgen-regulated protein (Kap) gene. After androgen withdrawal, androgen-induced Kap mRNA levels in PCT-SHBG cells are maintained for more than 2 wk vs 2 d in parental PCT cells. Transcriptome profiling after testosterone or DHT pretreatments, followed by 3 d of steroid withdrawal, also demonstrated that intracellular SHBG enhances androgen-dependent stimulation (e.g. Adh7, Vcam1, Areg, Tnfaip2) or repression (e.g. Cldn2 and Osr2) of many other genes in PCT cells. In addition, nuclear localization of the androgen receptor is enhanced and retained longer after steroid withdrawal in PCT cells containing functional SHBG. Thus, intracellular SHBG accentuates the uptake of androgens and sustains androgens access to the androgen receptor, especially under conditions of limited androgen supply.
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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".