کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
9943375 | 1573502 | 2005 | 14 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
SCFβ-TrCP1 Controls Smad4 Protein Stability in Pancreatic Cancer Cells
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موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
کاردیولوژی و پزشکی قلب و عروق
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چکیده انگلیسی
Smad4, also known as deleted in pancreatic carcinoma locus 4 (DPC4), is a critical co-factor in signal transduction pathways activated by transforming growth factor (TGF)-β-related ligands that regulate cell growth and differentiation. Mutations in Smad4/DPC4 have been identified in â¼50% of pancreatic adenocarcinomas. Here we report that SCFβ-TrCP1, a ubiquitin (E3) ligase, is a critical determinant for Smad4 protein degradation in pancreatic cancer cells. We found that F-box protein β-TrCP1 in this E3 ligase interacted with Smad4 and that SCFβ-TrCP1 inhibited TGF-β biological activity in pancreatic cancer cells by decreasing Smad4 stability. Very low Smad4 protein levels in human pancreatic ductal adenocarcinoma cells were observed by immunohistochemistry. By analyzing pancreatic tumor-derived Smad4 mutants, we found that most point-mutated Smad4 proteins, except those within or very close to a mutation cluster region, exhibited higher interaction affinity with β-TrCP1 and significantly elevated protein ubiquitination by SCFβ-TrCP1. Furthermore, AsPC-1 and Caco-2, two cancer cell lines harboring Smad4 point mutations, exhibited rapid Smad4 protein degradation due to the effect of SCFβ-TrCP1. Both Smad4 levels and TGF-β signaling were elevated by retrovirus-delivered β-TrCP1 siRNA in pancreatic cancer cells. Therefore, inhibition of Smad4-specific E3 ligase might be a target for therapeutic intervention in pancreatic cancer.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The American Journal of Pathology - Volume 166, Issue 5, May 2005, Pages 1379-1392
Journal: The American Journal of Pathology - Volume 166, Issue 5, May 2005, Pages 1379-1392
نویسندگان
Mei Wan, Jin Huang, Nirag C. Jhala, Ewan M. Tytler, Lei Yang, Selwyn M. Vickers, Yi Tang, Chongyuan Lu, Ning Wang, Xu Cao,