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1.
Oncogene ; 36(12): 1698-1706, 2017 03 23.
Article in English | MEDLINE | ID: mdl-27721409

ABSTRACT

Evasion of apoptosis allows many cancers to resist chemotherapy. Apoptosis is mediated by the serial activation of caspase family proteins. These proteases are often activated upon the release of cytochrome c from the mitochondria, which is promoted by the proapoptotic Bcl-2 family protein, Bax. This function of Bax is enhanced by the MOAP-1 (modulator of apoptosis protein 1) protein in response to DNA damage. Previously, we reported that MOAP-1 is targeted for ubiquitylation and degradation by the APC/CCdh1 ubiquitin ligase. In this study, we identify the HECT (homologous to the E6-AP carboxyl terminus) family E3 ubiquitin ligase, UBR5, as a novel ubiquitin ligase for MOAP-1. We demonstrate that UBR5 interacts physically with MOAP-1, ubiquitylates MOAP-1 in vitro and inhibits MOAP-1 stability in cultured cells. In addition, we show that Dyrk2 kinase, a reported UBR5 interactor, cooperates with UBR5 in mediating MOAP-1 ubiquitylation. Importantly, we found that cisplatin-resistant ovarian cancer cell lines exhibit lower levels of MOAP-1 accumulation than their sensitive counterparts upon cisplatin treatment, consistent with the previously reported role of MOAP-1 in modulating cisplatin-induced apoptosis. Accordingly, UBR5 knockdown increased MOAP-1 expression, enhanced Bax activation and sensitized otherwise resistant cells to cisplatin-induced apoptosis. Furthermore, UBR5 expression was higher in ovarian cancers from cisplatin-resistant patients than from cisplatin-responsive patients. These results show that UBR5 downregulates proapoptotic MOAP-1 and suggest that UBR5 can confer cisplatin resistance in ovarian cancer. Thus UBR5 may be an attractive therapeutic target for ovarian cancer treatment.


Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Antineoplastic Agents/pharmacology , Apoptosis Regulatory Proteins/metabolism , Cisplatin/pharmacology , Drug Resistance, Neoplasm , Ovarian Neoplasms/metabolism , Ubiquitin-Protein Ligases/metabolism , Apoptosis/genetics , Cell Line, Tumor , Drug Resistance, Neoplasm/genetics , Female , Humans , Multiprotein Complexes/metabolism , Ovarian Neoplasms/genetics , Protein Binding , Protein Stability , Proteolysis , Signal Transduction , Ubiquitin-Protein Ligases/genetics , Ubiquitination
2.
Oncogene ; 34(25): 3264-72, 2015 Jun.
Article in English | MEDLINE | ID: mdl-25151963

ABSTRACT

Blockade of fatty acid synthase (FASN), a key enzyme involved in de novo lipogenesis, results in robust death of ovarian cancer cells. However, known FASN inhibitors have proven to be poor therapeutic agents due to their ability to induce cachexia. Therefore, we sought to identify additional targets in the pathway linking FASN inhibition and cell death whose modulation might kill ovarian cancer cells without the attendant side effects. Here, we show that the initiator caspase-2 is required for robust death of ovarian cancer cells induced by FASN inhibitors. REDD1 (also known as Rtp801 or DDIT4), a known mTOR inhibitor previously implicated in the response to FASN inhibition, is a novel caspase-2 regulator in this pathway. REDD1 induction is compromised in ovarian cancer cells that do not respond to FASN inhibition. Inhibition of FASN induced an ATF4-dependent transcriptional induction of REDD1; downregulation of REDD1 prevented orlistat-induced activation of caspase-2, as monitored by its cleavage, proteolytic activity and dimerization. Abrogation of REDD1-mediated suppression of mTOR by TSC2 RNAi protected FASN inhibitor-sensitive ovarian cancer cells (OVCA420 cells) from orlistat-induced death. Conversely, suppression of mTOR with the chemical inhibitors PP242 or rapamycin-sensitized DOV13, an ovarian cancer cell line incapable of inducing REDD1, to orlistat-induced cell death through caspase-2. These findings indicate that REDD1 positively controls caspase-2-dependent cell death of ovarian cancer cells by inhibiting mTOR, placing mTOR as a novel upstream regulator of caspase-2 and supporting the possibility of manipulating mTOR to enhance caspase-2 activation in ovarian cancer.


Subject(s)
Caspase 2/metabolism , Cysteine Endopeptidases/metabolism , Fatty Acid Synthases/antagonists & inhibitors , Ovarian Neoplasms/enzymology , Ovarian Neoplasms/pathology , Activating Transcription Factor 4/metabolism , Caspase 2/chemistry , Cell Death/drug effects , Cell Line, Tumor , Cysteine Endopeptidases/chemistry , Enzyme Activation/drug effects , Enzyme Inhibitors/pharmacology , Female , Humans , Lactones/pharmacology , Orlistat , Protein Multimerization/drug effects , Protein Structure, Quaternary , RNA Interference , TOR Serine-Threonine Kinases/antagonists & inhibitors , Transcription Factors/metabolism , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/deficiency , Tumor Suppressor Proteins/genetics
4.
Wei Sheng Wu Xue Bao ; 29(3): 216-21, 1989 Jun.
Article in Chinese | MEDLINE | ID: mdl-2675472

ABSTRACT

A strain of Enteroinvasive Escherichia coli was isolated from the stool with blood and mucus of a child suffering from acute diarrhea. The strain shows the following characteristics: rapid fermentation of glucose (with gas), no fermentation of lactose, beta-galactosidase reaction positive, growth in acetate media, lysine decarboxylase negative, non-motility causing keratoconjunctivitis in guinea pigs and invading into epithelial cells, with a plasmid of 140 Md, Serotype is O121:H- which is a new serotype of Enteroinvasive Escherichia coli.


Subject(s)
Diarrhea/microbiology , Escherichia coli/isolation & purification , Feces/microbiology , Child , Escherichia coli/classification , Female , Humans , Serotyping
7.
Zhonghua Zhong Liu Za Zhi ; 7(4): 244-6, 1985 Jul.
Article in Chinese | MEDLINE | ID: mdl-4085311

ABSTRACT

Antithymocyte serum (ATS) is a kind of hetero-antiserum, many actions of which have been proved since 1974. Recently, we have transplanted several kinds of cell lines, including the diploid cells from human embryo lung (KMB 17,2BS) heteroploid cells (BHK21, FL) and malignant cells (BEL7404, Hela). Our experiments showed that malignant and heteroploid cells could be introduced into new born rats or mice under the effect of ATS and became transplanted tumour. However, in the rats or mice treated with ATS, the diploid cells could produce only necrotic or inflammatory nodules but not transplanted tumors. In recent years, a baby hamster kidney cell line (BHK21) has been applied in transformation assay. However, the experiments show that BHK21 cells, at 237 generations, have already become malignant cells, therefore, it can not be used for transformation assay. For BHK21 cell line, it is better to do the tumorigenicity test or to use earlier cells before the transformation assay. ATS method, used routinely to detect the malignant or normal cell lines, is worth extensive application.


Subject(s)
Antilymphocyte Serum , Animals , Cell Line , Cell Transformation, Neoplastic , Cricetinae , Mice , Neoplasm Transplantation , Neoplasms, Experimental/pathology , Rats
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