Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The AAA-ATPase thyroid hormone receptor interacting protein 13 (TRIP13), jointly with the Mad2-binding protein p31(comet), promotes the inactivation of the mitotic (spindle assembly) checkpoint by disassembling the mitotic checkpoint complex (MCC). This checkpoint system ensures the accuracy of chromosome segregation by delaying anaphase until correct bipolar attachment of chromatids to the mitotic spindle is achieved. MCC inhibits the anaphase-promoting complex/cyclosome (APC/C), a ubiquitin ligase that targets for degradation securin, an inhibitor of anaphase initiation. MCC is composed of the checkpoint proteins Mad2, BubR1, and Bub3, in association with the APC/C activator Cdc20. The assembly of MCC in active checkpoint is initiated by the conversion of Mad2 from an open (O-Mad2) to a closed (C-Mad2) conformation, which then binds tightly to Cdc20. Conversely, the disassembly of MCC that takes place when the checkpoint is turned off involves the conversion of C-Mad2 back to O-Mad2. Previously, we found that the latter process is mediated by TRIP13 together with p31(comet), but the mode of their interaction remained unknown. Here, we report that the oligomeric form of TRIP13 binds both p31(comet) and MCC. Furthermore, p31(comet) and checkpoint complexes mutually promote the binding of each other to oligomeric TRIP13. We propose that p31(comet) bound to C-Mad2-containing checkpoint complex is the substrate for the ATPase and that the substrate-binding site of TRIP13 is composed of subsites specific for p31(comet) and C-Mad2-containing complex. The simultaneous occupancy of both subsites is required for high-affinity binding to TRIP13.
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PMID:Mode of interaction of TRIP13 AAA-ATPase with the Mad2-binding protein p31comet and with mitotic checkpoint complexes. 2632 90

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, and systemic chemotherapy is the major treatment strategy for late-stage HCC patients. Poor prognosis following chemotherapy is the general outcome owing to recurrent resistance. Recent studies have suggested that in addition to cytotoxic effects on tumor cells, chemotherapy can induce an alternative cascade that supports tumor growth and metastasis. In the present investigation, we showed that thyroid hormone (TH), a potent hormone-mediating cellular differentiation and metabolism, acts as an antiapoptosis factor upon challenge of thyroid hormone receptor (TR)-expressing HCC cells with cancer therapy drugs, including cisplatin, doxorubicin and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TH/TR signaling promoted chemotherapy resistance through negatively regulating the pro-apoptotic protein, Bim, resulting in doxorubicin-induced metastasis of chemotherapy-resistant HCC cells. Ectopic expression of Bim in hepatoma cells challenged with chemotherapeutic drugs abolished TH/TR-triggered apoptosis resistance and metastasis. Furthermore, Bim expression was directly transactivated by Forkhead box protein O1 (FoxO1), which was negatively regulated by TH/TR. TH/TR suppressed FoxO1 activity through both transcriptional downregulation and nuclear exclusion of FoxO1 triggered by Akt-mediated phosphorylation. Ectopic expression of the constitutively active FoxO1 mutant, FoxO1-AAA, but not FoxO1-wt, diminished the suppressive effect of TH/TR on Bim. Our findings collectively suggest that expression of Bim is mediated by FoxO1 and indirectly downregulated by TH/TR, leading to chemotherapy resistance and doxorubicin-promoted metastasis of hepatoma cells.
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PMID:Chemotherapy resistance and metastasis-promoting effects of thyroid hormone in hepatocarcinoma cells are mediated by suppression of FoxO1 and Bim pathway. 2749 Sep 29

TRIP13 (thyroid hormone receptor interacting protein 13) AAA-ATPase has been reported to be involved in the metaphase checkpoint in human breast cancer, prostate cancer, and cervical cancer. However, the expression pattern and biologic role of TRIP13 in non-small cell lung cancer (NSCLC) remained unknown. In our present study, real-time PCR and western blot were used to detect the expression level of TRIP13 in NSCLC tissues and cell lines. We found that the expression levels of TRIP13 mRNA and protein were significantly upregulated in cell lines and lung tissues. Knockdown of TRIP13 by lentivirus inhibited cell proliferation and invasion in both A549 and H1299 cells. Furthermore, flow cytometry, western blot and immunoprecipitation showed that the MCC complex was disassembled and cells became arrested in metaphase, when TRIP13 was inhibited. In conclusion, here we first report that TRIP13 acts as a tumor promoter in regulating cell proliferation, invasion, and cell cycle checkpoint in NSCLC cells and may be a clinically useful marker for the diagnosis and treatment of lung cancer.
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PMID:The oncogenic role of TRIP13 in regulating proliferation, invasion, and cell cycle checkpoint in NSCLC cells. 3193 78