Gonadotropin-stimulated epidermal growth factor receptor expression in human ovarian surface epithelial cells: involvement of cyclic AMP-dependent exchange protein activated by cAMP pathway
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Bibliographic record
Abstract
In addition to their critical roles in folliculogenesis and ovarian granulosa cell steroidogenesis, gonadotropins have been implicated as potential risk factors in ovarian epithelial carcinomas, most of which are derived from ovarian surface epithelium (OSE). However, the molecular mechanism underlying the effects of FSH and LH in OSE and its neoplastic counterpart is not well understood. We previously demonstrated that gonadotropins promote the growth of OSE cells by regulating the levels of epidermal growth factor receptor (EGFR) via the activation of ERK1/2 and PI3K pathways in immortalized human OSE (IOSE) cells. In this study, we investigated whether cAMP and its novel binding target, named exchange protein activated by cAMP (Epac), are involved in the gonadotropin-induced EGFR expression in OSE cells. Gonadotropins elevated intracellular cAMP levels in both IOSE and granulosa cells, and this increase was attenuated by SQ22536, an inhibitor of adenylyl cyclase (AC). The activation of the ERK1/2 and Akt pathways as well as the expression of EGFR was stimulated by reagents that elevate intracellular cAMP levels, via cAMP analog 8-bromo-cAMP and AC activator forskolin. A similar increase was observed when the cells were treated with a novel cAMP analog, 8-(4-chlorophenylthio)-2'-O-methyl adenosine-3',5'-cyclic monophosphate (8-CPT-2ME-cAMP), which activates Epac specifically but not PKA. Moreover, the gonadotropin-induced EGFR expression and ERK1/2 and Akt activation were abolished by overexpression of dominant negative Epac. Taken together, these results indicate that the AC/cAMP/Epac signaling pathway may mediate the up-regulation of EGFR by gonadotropins via ERK1/2 and Akt activation.
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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