Potential Role of Jun Activation Domain–Binding Protein 1 as a Negative Regulator of p27kip1 in Pancreatic Adenocarcinoma
| العنوان: | Potential Role of Jun Activation Domain–Binding Protein 1 as a Negative Regulator of p27kip1 in Pancreatic Adenocarcinoma |
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| المؤلفون: | Francois Xavier Claret, Douglas B. Evans, Qingxiu Zhang, Paul J. Chiao, Maria A. Kouvaraki, Linus Ho, Anita L. Korapati, Ling Tian, George Z. Rassidakis |
| المصدر: | Cancer Research. 66:8581-8589 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2006. |
| سنة النشر: | 2006 |
| مصطلحات موضوعية: | Adult, Male, Cancer Research, Small interfering RNA, Pancreatic disease, Tumor suppressor gene, Adenocarcinoma, Biology, Article, Pancreatic cancer, Coactivator, medicine, Homeostasis, Humans, Pancreas, Aged, Oligonucleotide Array Sequence Analysis, COP9 Signalosome Complex, Intracellular Signaling Peptides and Proteins, Middle Aged, medicine.disease, Combined Modality Therapy, Immunohistochemistry, Pancreatic Neoplasms, medicine.anatomical_structure, Oncology, Cancer research, Female, CA19-9, Cyclin-Dependent Kinase Inhibitor p27, Peptide Hydrolases |
| الوصف: | Reduced expression of p27 has been associated with poor prognosis in most human cancers, including pancreatic adenocarcinoma. Jun activation domain–binding protein 1 (JAB1), an activator protein (AP-1) coactivator, previously implicated in p27 degradation, is overexpressed in various tumors and correlates with low p27 expression. We examined JAB1 and p27 in normal and neoplastic pancreatic tissues. Increased JAB1 expression was seen in pancreatic carcinoma samples but not in paired normal pancreatic tissues. Immunohistochemical analysis using tissue microarrays showed that JAB1 was overexpressed in all 32 (100%) pancreatic adenocarcinoma samples tested, predominantly nuclear in 23 (72%) samples and predominantly cytoplasmic in 9 (28%) tumors. When 10% was used as a cutoff for p27 positivity, p27 was expressed in 11 (34%) of tumors; however, p27 expression was localized in the nuclei of tumor cells in only 4 (13%) of the samples. Overexpression of the JAB1 in the pancreatic carcinoma cell lines Panc-1, Mia PaCa-2, and Panc-28 resulted in decreased p27 expression. Conversely, down-regulation of JAB1 by short interfering RNA substantially increased p27 expression and inhibited progression from G1 to S phase of the cell cycle. Interestingly, JAB1-mediated p27 degradation was not impaired when S-phase kinase-interacting protein 2 (Skp2), an F-box protein required for the ubiquitination and consequent degradation of p27, was silenced. Thus, JAB1 may have an Skp2-independent p27 degradation mechanism in pancreatic cancer cells. These findings suggest that JAB1 overexpression is involved in the pathogenesis of pancreatic cancer through JAB1-mediated p27 degradation and that control of JAB1 expression is a novel therapeutic target in patients with pancreatic adenocarcinomas. (Cancer Res 2006; 66(17): 8581-9) |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b4c4658d06212b5653167fbfbc1066b3 https://doi.org/10.1158/0008-5472.can-06-0975 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....b4c4658d06212b5653167fbfbc1066b3 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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