Autocrine motility factor receptor (AMFR) is a cell surface glycoprotein of molecular weight 78 000 (gp78), mediating cell motility signaling in vitro and metastasis in vivo. Here, we cloned the full-length cDNAs for both human and mouse AMFR genes. Both genes encode a protein of 643 amino acids containing a seven transmembrane domain, a RING-H2 motif and a leucine zipper motif and showed a 94.7% amino acid sequence identity to each other. Analysis of the amino acid sequence of AMFR with protein databases revealed no significant homology with all known seven transmembrane proteins, but a significant structural similarity to a hypothetical protein of Caenorhabditis elegans, F26E4.11. Thus, AMFR is a highly conserved gene which encodes a novel type of seven transmembrane protein.z 1999 Federation of European Biochemical Societies.
Autocrine motility factor (AMF) is a cytokine that regulates locomotion and metastasis of tumor cells. It is well known that expression levels of AMF secretion and its receptor (AMF R) are closely related to tumor malignancy and rheumatoid arthritis. We have established that AMF signaling induced anti-apoptotic activity and that human fibrosarcoma HT-1080 line that secreted high levels of AMF were resistant to drug-induced apoptosis. These cells did not express the apoptotic protease activating factor-1 (Apaf-1) and Caspase-9 genes that encode for the proteins that form the "apoptosome" complex. The disappearance of the Apaf-1 and Caspase-9 gene was recovered by a cellular signaling inhibitor of protein kinase C, phosphatidylinositol 3-phosphate kinase and mitogen-activated protein kinase of the in vitro apoptosome Cancer is a disease in which down-regulation of apoptosis often occurs, and this often appears to compromise chemotherapy using anti-cancer drugs. It is well known that abnormal regulation of many mitochondria-related factors, such as Bcl-2, cytochrome c, Bax, Bik, Mn SOD, APAF-1 and Caspase-9, is observed in cancer cells. For example, the lack or loss of apoptotic proteinase activating factor-1 (Apaf-1) was observed in metastatic melanomas, which can contend with chemotherapy and are unable to execute the typical apoptotic programme in response to p53 activation. 1 Sensitivity to apoptosis induced by UV light dependent on its Apaf-1 deficiency level, 2 and over-expression of Apaf-1 induced etoposide-or paclitaxel-sensitive apoptosis, 3,4 have been reported in human leukemia cell lines. However, over-expression or experimental transduction of Apaf-1 and caspase-9 genes promoted the apoptotic sensitivities to radiation or the chemotherapeutic index of glioma cells. [5][6][7] Thus, the expression levels of Apaf-1 and caspase-9 in tumor cells seem to be important factors in determining the malignancy of the cells, and control of their expression may produce a therapeutic effect in clinical cancer treatments such as radiation and anti-cancer drugs. 8,9 Apaf-1 and caspase-9 are the core proteins of the "apoptosome" complex, which has an essential role in inducing mitochondrial programmed cell death. 10 It is necessary for the activation of pro-caspase-9 that cytochrome c and dATP interact with Apaf-1 as cofactors, and then the activated caspase-9 turns on the effector caspase-3 that then kills the cell by proteolysis. 11 Therefore, the apoptosome is a key molecular event of programmed cell death in several diseases that express an unusual apoptotic regulation, such as cancer. The function of the apoptosome is controlled by multiple molecules, transforming growth factor-beta up regulation via cytochrome c release, 12 heat shock protein 70 and 90 downregulation by binding to Apaf-1 and the formation of a cytosolic complex. [13][14][15] However, it is poorly understood at the molecular level why Apaf-1 and caspase-9 are decreased in malignant cells and how they regulate the function of the apoptosome. Ke...
Phosphoglucose isomerase (PGI) is a multifunctional enzyme that functions in glucose metabolism as a glycolytic enzyme catalyzing an interconversion between glucose and fructose inside the cell, while it acts as cytokine outside the cell, with properties that include autocrine motility factor (AMF)-regulating tumor cell motility. Overexpression of AMF/PGI induces epithelial-to-mesenchymal transition with enhanced malignancy. Recent studies have revealed that silencing of AMF/PGI resulted in mesenchymal-to-epithelial transition (MET) of human lung fibrosarcoma cells and breast cancer cells with reduced malignancy. Here, we constructed a hammerhead ribozyme specific against GUC triplet at the position G390 in the human, mouse, and rat AMF/PGI mRNA sequence. Mesenchymal human osteosarcoma MG-63, HS-Os-1, and murine LM8 cells were stably transfected with the ribozyme specific for AMF/PGI. The stable transfectant cells showed effective downregulation of AMF/PGI expression and subsequent abrogation of AMF/PGI secretion, which resulted in morphologic change with reduced growth, motility, and invasion. Silencing of AMF/PGI induced MET, in which upregulation of E-cadherin and cytokeratins, as well as downregulation of vimentin, were noted. The MET guided by AMF/PGI gene silencing induced osteosarcoma MG-63 to terminally differentiate into mature osteoblasts. Furthermore, MET completely suppressed the tumor growth and pulmonary metastasis of LM8 cells in nude mice. Thus, acquisition of malignancy might be completed in part by upregulation of AMF/PGI, and waiver of malignancy might also be controlled by downregulation of AMF/PGI. Cancer Res; 70(22); 9483-93. ©2010 AACR.
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