Drug-specific pattern of P53 phosphorylation in endometrial cancer cells
Bibliographic record
Abstract
AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 3346 Background : Following cellular insults causing DNA damage or microtubule disruption, P53 plays a crucial role in determining cell fate. When it is not sequestered by MDM2, it can induce the expression of factors that stop cell cycle progression to allow DNA damage repair. P53 has also been shown to induce apoptosis if DNA damage is too severe. P53 tumor suppresssor gene is frequently mutated in cancer cells, which favours cancer development. P53 activity is also known to be regulated at the post-transcriptional level, since wild-type and mutated P53 proteins can be phosphorylated on multiple serine residues. Phosphorylation on particular serine residues has been shown to regulate binding of P53 to MDM2, or its gene transactivation activity. Human endometrial tumors often show resistance to current anticancer agents such as cisplatin, doxorubicin and taxol in the clinic, and this is in part attributable to altered P53 activity. We have observed that endometrial cancinoma cell lines (which have a mutated P53 protein) show distinct sensitivity to the three drugs in vitro . Given that mutations occur in the same region of p53 gene in these cells, the P53 status is not likely to be responsible for drug-specific sensitivity. However, considering that the three drugs have different mode of action, we hypothesized that they could induce different patterns of P53 phosphorylation in endometrial cancer cells, thereby differently modulating P53 activity and chemosensitivity. The present study aimed at determining the patterns of P53 phosphorylation in endometrial cancer cells in response to the three drugs. Methods : Five endometrial cancer cell lines (KLE, Ishikawa, HEC-1A, RL-95-2, EN-1078D) were treated for short time periods with cisplatin, doxorubicin or paclitaxel, and we analyzed early events of phosphorylation on key serine residues of P53, using Western Blot. Results : In three out of five cell lines (HEC-1A, RL-95-2, KLE), cisplatin and doxorubicin, but not taxol, induced P53 phosphorylation on serine 15, 20 and 37. In all cases, doxorubicin induced a higher extent of P53 phosphorylation than cisplatin. Doxorubicin, but not cisplatin, also induced phosphorylation on serine 9, in HEC-1A cells. Paclitaxel, but not cisplatin or doxorubicin, induced the phophorylation of P53 on serine 46, but not on other serines (9, 15, 20, 37). Conclusion : These preliminary results suggest that different chemotherapeutic drugs can induce different patterns of phosphorylation of P53 in endometrial carcinoma cells suggesting this might be a crucial event dictating drug-specific chemosensivity.
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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) | 0.002 | 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".