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학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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Aberrant activation of Ras has been implicated in aggressiveness of breast cancer. Among Ras isoforms (H-, K-, and N-), H-Ras has been known to be primarily responsible for invasion and metastasis of breast cancer cells. Phosphorylation of serine (Ser) or threonine (Thr) is a key regulatory mechanism responsible for controlling activities and functions of various proteins involved in intracellular signal transduction. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, Pin1 changes the conformation of a subset of proteins phosphorylated on Ser/Thr that precedes proline (Pro). In this study we have found that Pin1 is highly overexpressed in human breast tumor tissues and H-Ras transformed human mammary epithelial (H-Ras MCF10A) and MDA-MB-231 breast cancer cells. Notably, Pin1 directly bound to the activated form of H-Ras harbouring a Ser/Thr-Pro motif. Pharmacologic inhibition of Pin1 reduced clonogenicity of MDA-MB-231 human breast cancer cells. Paclitaxel accelerates apoptosis in Pin1 silenced H-Ras MCF10A cells. MDR genes (MDR1 and MRP4) were significantly downregulated in MDA-MB-231 cells stably silenced for Pin1. We speculate that Pin1 interacts with GTP-H-Ras, thereby upregulating the expression of drug resistance genes, which confers survival advantage and aggressiveness of breast cancer cells under chemotherapy. Key Words Breast neoplasm, Drug resistance, H-Ras, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1
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참고문헌 (45)
참고문헌 신청
Lu PJ / 2002 / Critical role of WW domain phosphorylation in regulating phosphoserine binding activity and Pin1 function / J Biol Chem 277:2381~2384
Ryo A / 2001 / Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC / Nat Cell Biol 3:793~801
Ryo A / 2002 / PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells / Mol Cell Biol 22:5281~5295
Bao L / 2004 / Prevalent overexpression of prolyl isomerase Pin1 in human cancers / Am J Pathol 164:1727~1737
Wulf GM / 2001 / Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1 / EMBO J 20:3459~3472
Ryo A / 2001 / Pin1 regulates turnover and subcellular localization of beta-catenin by inhibiting its interaction with APC / Nat Cell Biol 3:793~801
Ryo A / 2002 / PIN1 is an E2F target gene essential for Neu/Ras-induced transformation of mammary epithelial cells / Mol Cell Biol 22:5281~5295
Bao L / 2004 / Prevalent overexpression of prolyl isomerase Pin1 in human cancers / Am J Pathol 164:1727~1737
Wulf GM / 2001 / Pin1 is overexpressed in breast cancer and cooperates with Ras signaling in increasing the transcriptional activity of c-Jun towards cyclin D1 / EMBO J 20:3459~3472
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