Angiogenin (ANG) is a secreted ribonuclease that cleaves tRNA to initiate a stress-response program in mammalian cells. Here we show that ANG inhibits protein synthesis and promotes arsenite-and pateamine A-induced assembly of stress granules (SGs). These effects are abrogated in cells transfected with the ANG inhibitor RNH1. Transfection of natural or synthetic 5-but not 3-tRNA fragments (tRNA-derived stress-induced RNAs; tiRNAs) induces the phospho-eukaryotic translation initiation factor 2␣-independent assembly of SGs. Natural 5-tiRNAs but not 3-tiRNAs are capped with a 5-monophosphate that is required for optimal SG assembly. These findings reveal that SG assembly is a component of the ANG-and tiRNA-induced stress response program.In response to environmental stress, eukaryotic cells activate stress response programs that down-regulate energy-expensive processes, such as transcription and translation. These regulatory programs reduce the expression of common housekeeping genes while increasing the expression of genes that repair stress-induced damage and promote cell survival. At the level of translation, this is achieved by exploiting the differential sensitivity of mRNAs to changes in the availability or activity of general initiation factors, such as eukaryotic translation initiation factor 2␣ (eIF2␣) 3 (1). Phosphorylation of eIF2␣ by one of several stress-activated kinases reduces the availability of the eIF2-GTP-tRNA i Met ternary complex to inhibit translation initiation. This reduces the translation of most transcripts but enhances the translation of transcripts possessing regulatory upstream open reading frames, such as transcription factor ATF4, a component of the integrated stress response program.Thus, phospho-eIF2␣ triggers a profound reprogramming of cellular protein synthesis that helps cells adapt to adverse environmental conditions.Stress-induced cleavage of tRNA initiates a complementary stress response program found in both prokaryotes and eukaryotes (2). In mammals, stress-induced tRNA cleavage is mediated by angiogenin (ANG) (3, 4), a 14-kDa member of the pancreatic RNase superfamily. ANG is a secreted endoribonuclease that possesses both angiogenic (5) and cytoprotective activities (6, 7). Secreted ANG enters cells via receptor-mediated endocytosis (8, 9), translocates to the nucleus (10), and promotes ribosomal RNA transcription and cellular proliferation (11-13). ANG secretion is stimulated by hypoxia, suggesting that it may serve as a stress-induced paracrine factor that protects neighboring cells from deleterious effects of stress.In a previous study, we showed that stress promotes ANGmediated tRNA cleavage to produce tRNA-derived stress-induced RNAs (tiRNAs) (4). Cleavage occurs preferentially in the anticodon loop of mature tRNA to produce 5Ј-and 3Ј-fragments (5Ј-and 3Ј-tiRNAs, respectively). The addition of recombinant wild type but not RNase-inactive mutant ANG to cultured cells promotes tiRNA production and inhibition of protein synthesis. Thus, the ribonuclease activity of ANG...

The role of epithelial-mesenchymal transition (EMT) in metastasis remains controversial. EMT has been postulated as an absolute requirement for tumor invasion and metastasis. Three different models including incomplete EMT, mesenchymal-epithelial transition (MET), and collective migration have been proposed for the role of EMT in cancer invasion and metastasis. However, skepticism remains about whether EMT truly occurs during cancer progression, and if it does, whether it plays an indispensible role in metastasis. Our recent findings suggest that EMT cells are responsible for degrading the surrounding matrix to enable invasion and intravasation of both EMT and non-EMT cells. Only non-EMT cells that have entered the blood stream are able to reestablish colonies in the secondary sites. Here, we discuss an alternative model for the role of EMT in cancer metastasis in which EMT and non-EMT cells cooperate to complete the entire process of spontaneous metastasis. [Cancer Res 2009;69(18):7135-9] Epithelial-Mesenchymal Transition and Cancer MetastasisEpithelial-mesenchymal transition (EMT) was first recognized as a central differentiation process in early embryogenic morphogenesis (1). It is a coordinated molecular and cellular change defined as a reduction in cell-cell adhesion, apical-basolateral polarity, and epithelial markers, as well as an acquisition of motility, spindle-cell shape, and mesenchymal markers. The definition of EMT in embryo development, which includes an ordered series of transcriptional events and a switch in cell fate, has not been strictly followed in cancer research, in which this term has been more liberally referred to as a recognizable change in cellular phenotype characterized as loss of cell junctions and gain of migratory behaviors (2).This more inclusive EMT process has been proposed and supported by numerous publications to be a potent mechanism that enhances the detachment of cancer cells from primary tumors. However, it is still controversial whether transformation of a noninvasive tumor into a metastatic tumor truly represents an EMT, and if it is, how important it is in the process of cancer metastasis (3, 4). The main argument for the lack of a role of EMT in cancer is that metastases seem histopathologically similar to the primary tumors from which they are derived. To resolve this apparent contradiction, a mesenchymal-epithelial transition (MET) process in the metastatic sites has been postulated as part of the process of metastatic tumor formation (5). MET is an attractive hypothesis that can explain the histopathological similarity between primary and metastatic tumors. In support of the MET hypothesis, dynamic expression of E-cadherin (CDH1) in cancer progression has been documented. However, direct experimental data supporting MET in cancer metastasis are still lacking. For example, Graff and colleagues showed that the DNA methylation status of the CDH1 promoter varies at different stages of the metastatic process (6). In primary breast cancers, the tumor cells ...

No abstract

We provide the first evidence that ANG mutations, identified in ALS patients, are associated with functional loss of ANG activity. Moreover, strong ANG expression, in normal human fetal and adult spinal cord neurons and endothelial cells, confirms the plausibility of ANG dysfunction being relevant to the pathogenesis of ALS.