دورية أكاديمية
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Inhibition of MKK7-JNK by the TOR signaling pathway regulator-like protein contributes to resistance of HCC cells to TRAIL-induced apoptosis.

التفاصيل البيبلوغرافية
العنوان: Inhibition of MKK7-JNK by the TOR signaling pathway regulator-like protein contributes to resistance of HCC cells to TRAIL-induced apoptosis.
المؤلفون: Song IS; Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea; Cardiovascular and Metabolic Disease Center, Inje University, Busan, South Korea., Jun SY; Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea; Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea., Na HJ; Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea; Renal Division, Brigham and Women's Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts., Kim HT; Department of Biology, Chungnam National University, Daejeon, South Korea., Jung SY; Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea., Ha GH; Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea., Park YH; Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea; Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea., Long LZ; Department of Pathology, School of Medicine, Chungnam National University, Daejeon, South Korea., Yu DY; Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea; Aging Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea., Kim JM; Department of Pathology, School of Medicine, Chungnam National University, Daejeon, South Korea., Kim JH; Department of Pathology, Eulji University School of Medicine, Daejeon, South Korea., Ko JH; Daejeon-KRIBB-FHCRC Research Cooperation Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea., Kim CH; Department of Biology, Chungnam National University, Daejeon, South Korea. Electronic address: zebrakim@cnu.ac.kr., Kim NS; Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, South Korea; Department of Functional Genomics, University of Science and Technology, Daejeon, South Korea. Electronic address: nskim37@kribb.re.kr.
المصدر: Gastroenterology [Gastroenterology] 2012 Nov; Vol. 143 (5), pp. 1341-1351. Date of Electronic Publication: 2012 Jul 27.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: W.B. Saunders Country of Publication: United States NLM ID: 0374630 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1528-0012 (Electronic) Linking ISSN: 00165085 NLM ISO Abbreviation: Gastroenterology Subsets: MEDLINE
أسماء مطبوعة: Publication: Philadelphia, PA : W.B. Saunders
Original Publication: Baltimore.
مواضيع طبية MeSH: Carcinoma, Hepatocellular/*metabolism , Intracellular Signaling Peptides and Proteins/*metabolism , JNK Mitogen-Activated Protein Kinases/*metabolism , Liver Neoplasms/*metabolism , MAP Kinase Kinase 7/*metabolism, Animals ; Apoptosis ; Carcinoma, Hepatocellular/genetics ; Female ; Gene Knockdown Techniques ; Hep G2 Cells ; Hepatocytes/metabolism ; Humans ; Intracellular Signaling Peptides and Proteins/genetics ; Liver/metabolism ; Liver Neoplasms/genetics ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Protein Phosphatase 2/metabolism ; RNA, Messenger/metabolism ; RNA, Small Interfering ; Signal Transduction ; TNF-Related Apoptosis-Inducing Ligand/metabolism ; Up-Regulation ; Zebrafish/embryology ; Zebrafish/genetics ; Zebrafish/metabolism
مستخلص: Background & Aims: The TOR signaling pathway regulator-like (TIPRL) protein, the mammalian ortholog of yeast TIP41, was identified in an expression profiling screen for factors that regulate human liver carcinogenesis. We investigated the role of human TIPRL protein in hepatocellular carcinoma (HCC).
Methods: We measured the level of TIPRL in HCC and adjacent nontumor tissues from patients. We used small interfering RNAs and zebrafish to study the function of TIPRL. We used annexin V propidium iodide staining and immunoblot analyses to measure apoptosis and activation of apoptotic signaling pathways. We used confocal microscopy, coimmunoprecipitation, and glutathione-S transferase pull-down analyses to determine interactions among mitogen-activated protein kinase kinase 7 (MKK7 or MAP2K7), TIPRL, and the protein phosphatase type 2A (PP2Ac). We studied the effects of TIPRL in tumor xenografts in mice.
Results: Levels of TIPRL were higher in HCC tissues and cell lines than nontumor tissues and primary hepatocytes. Knockdown of tiprl expression in zebrafish led to large amounts of apoptosis throughout the embryos. Incubation of HCC cells, but not primary human hepatocytes, with small interfering RNA against TIPRL (siTIPRL) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) caused prolonged activation (phosphorylation) of MKK7 and c-Jun N-terminal kinase (JNK) and led to apoptosis, indicated by cleavage of procaspase-8,-3 and of poly-(adenosine diphosphate-ribose) polymerase. TIPRL bound to MKK7 and PP2Ac and promoted the interaction between MKK7 and PP2Ac. In mice, injection of HCC xenograft tumors with siTIPRL and TRAIL led to tumor apoptosis and regression.
Conclusions: TIPRL is highly up-regulated in human HCC samples and cell lines, compared with noncancerous liver tissues. TIPRL prevents prolonged activation of MKK7 and JNK and TRAIL-induced apoptosis by mediating the interaction between MKK7 and PP2Ac.
(Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)
المشرفين على المادة: 0 (Intracellular Signaling Peptides and Proteins)
0 (RNA, Messenger)
0 (RNA, Small Interfering)
0 (TIPRL protein, human)
0 (TNF-Related Apoptosis-Inducing Ligand)
0 (TNFSF10 protein, human)
EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
EC 2.7.12.2 (MAP Kinase Kinase 7)
EC 2.7.12.2 (MAP2K7 protein, human)
EC 3.1.3.16 (Protein Phosphatase 2)
تواريخ الأحداث: Date Created: 20120731 Date Completed: 20130114 Latest Revision: 20180623
رمز التحديث: 20231215
DOI: 10.1053/j.gastro.2012.07.103
PMID: 22841785
قاعدة البيانات: MEDLINE
الوصف
تدمد:1528-0012
DOI:10.1053/j.gastro.2012.07.103