Nuclear translocation of angiogenin in proliferatingendothelial cells is essential to its angiogenic activity.

Moroianu, Junona; Riordan, James

doi:10.1073/pnas.91.5.1677

Cited by 245 publications

(257 citation statements)

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“…VEGF was detected in the nuclear fraction, which may reflect minor contamination of this fraction during preparation and/or translocation of VEGF into the nucleus (Moroianu 1994). It is less likely to represent artefact as there was a wide variation in expression in the nuclear fractions prepared from different tumours, with no relationship to total cellular VEGF protein levels.…”

Section: Discussionmentioning

confidence: 98%

Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E

Scott

Smith²,

Poulsom³

et al. 1998

Br J Cancer

102

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Summary Angiogenesis is the formation of new blood vessels from the existing vasculature. Vascular endothelial growth factor (VEGF) is an endothelium-specific angiogenic factor strongly implicated in pathological angiogenesis. In this study, the mRNA and protein expression of the four alternatively spliced VEGF isoforms (121, 165, 189 and 206 amino acids) were examined in normal and malignant breast tissues. Three VEGF transcripts were detected in both (121>165>189), whereas only VEGF165 protein was detected. The tumours expressed more VEGF mRNA (P = 0.02) and protein (P < 0.0001), with eight-fold more VEGF protein generated per mRNA unit (P = 0.009). To examine this further, the expression of elF-4E, a translation initiation factor, was examined. Increased elF-4E mRNA levels were detected in the tumours (P < 0.0001) that correlated with VEGF mRNA (P = 0.0002), implying co-regulation of these genes. VEGF mRNA expression was elevated in tumours expressing the epidermal growth factor receptor (P < 0.01), but there was no difference according to oestrogen receptor status (P = 0.9), node status (P = 0.09) or between differing histologies (P = 0.4). These data suggest that elevated VEGF protein expression, by both enhanced transcription and translation, is a potential means by which tumour angiogenesis is induced in breast carcinomas. VEGF expression is also significantly associated with factors correlating with a poor outcome, implying a role in progression of this disease.Keywords: angiogenesis; vascular endothelial growth factor; elF-4E translation; breast cancer; GAPDH Angiogenesis is the formation of new blood vessels from the existing vasculature. It is a complex process involving degradation of the basement membrane, endothelial proliferation, migration, tube formation and the initiation of blood flow. Angiogenesis occurs in a wide range of biological events, including the female reproductive cycle, embryonic development and wound healing (Folkman and Shing, 1992). In the pathological setting, it is an important component of many diseases including rheumatoid arthritis and diabetic retinopathy, and is a critical, although not the only, step necessary for the growth and metastasis of tumours (Folkman, 1990). Under physiological conditions, angiogenesis is regulated strictly by a balance of stimulation and inhibition, but in the neoplastic state there appears to be a loss of control (Liotta et al, 1991).Although several types of angiogenic factors, including lipids and peptides, have been identified (reviewed Folkman and Klagsbrun, 1987;Bicknell and Harris, 1991;Bouck, 1993;Scott and Harris, 1994), the focus has remained on the polypeptide growth factors. Of these, the angiogenic growth factor most strongly implicated in tumour angiogenesis is vascular endothelial growth factor (VEGF).In addition to being the most selective endothelial mitogen known (Leung et al, 1989), VEGF elicits other effects on endothelial cells, including chemotaxis (Kock et al, 1994), increased permeability (Keck et al, 1989)

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Section: Discussionmentioning

confidence: 98%

Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E

Scott

Smith²,

Poulsom³

et al. 1998

Br J Cancer

102

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“…Although Arg31 is not involved in enzymatic activity, it is part of a nuclear translocation sequence, 31 RRRGL 35 , that is essential for angiogenic activity (23,24). R31A is translocated less efficiently than the native protein (23), and it is somewhat less effective than wild-type ANG at inducing angiogenesis (51).…”

Section: Discussionmentioning

confidence: 99%

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

et al. 2007

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Human angiogenin (ANG), the first member of the angiogenin family (from the pancreatic ribonuclease A superfamily) to be identified, is an angiogenic factor that induces neovascularization. It has received much attention due to its involvement in the growth of tumors and its elevated expression level in pancreatic and several other cancers. Recently the biological role of ANG has been shown to extend to the nervous system. Mutations in ANG have been linked with familial as well as sporadic forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by selective destruction of motor neurons. Furthermore, mouse angiogenin-1 has been shown to be expressed in the developing nervous system and during the neuronal differentiation of pluripotent stem cells. We have now characterized the seven variants of ANG reported in ALS patients with respect to the known biochemical properties of ANG and further studied the biological properties of three of these variants. Our results show that the ribonucleolytic activity of six of the seven ANG-ALS implicated variants is significantly reduced or lost and some variants also show altered thermal stability. We report a significant reduction in the cell proliferative and angiogenic activities of the three variants that we chose to investigate further. Our studies on the biochemical and structural features of these ANG variants now form the basis for further investigations to determine their role(s) in ALS.Amyotrophic lateral sclerosis (ALS) 1 is a fatal neurodegenerative disorder characterized by selective destruction of motor neurons (1). In the past decade, a small number of genes involved in the etiology of the disease have been identified (for a recent review see ref 2). The best studied of these is SOD1 (3), the gene for Cu/Zn superoxide dismutase. More than a hundred SOD1 mutations have now been linked with ALS, and motor neuron death from many of these mutations has been shown to result from a toxic gain of function rather than loss of dismutase activity. However, mutations in SOD1 account for only 1-2% of all cases of ALS and 20% of the familial cases. Some of the other proteins implicated in ALS are the vesicle-trafficking protein VAPB (4); ALSIN, a putative guanine nucleotide factor for GTPase (5); and senataxin (6). In addition, vascular endothelial growth factor (VEGF), an angiogenic factor that plays an important role in motor neuron survival, has been linked with ALS (7-10). However, the causes and molecular mechanisms underlying ALS are still largely unclear, and effective therapies do not appear to be imminent. Angiogenin (ANG), which encodes an angiogenic protein, was recently identified as a candidate susceptibility gene for ALS in the Irish and Scottish population by Greenway et al. (11). In a further study of over 2500 individuals from five independent populations from northern Europe and North America, Greenway et al. (12) found seven missense mutations (Figure 1) in 11 unrelated individuals with sporadic ALS and in f...

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“…Despite retaining only 10 Ϫ5 -to 10 Ϫ6 -fold the activity of RNase A, the weak RNase activity of angiogenin is critical to its angiogenic activity (Shapiro and Vallee, 1989;Leland et al, 2002). The majority of mutations that segregate with ALS do not significantly alter the secondary structure or stability of the protein, but rather disrupt its RNase function or subcellular distribution (Moroianu and Riordan, 1994;Leland et al, 2002;Greenway et al, 2006;Crabtree et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

Skorupa

King²,

Aparicio³

et al. 2012

J. Neurosci.

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Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disorder affecting motoneurons. Mutations in angiogenin, encoding a member of the pancreatic RNase A superfamily, segregate with ALS. We previously demonstrated that angiogenin administration shows promise as a neuroprotective therapeutic in studies using transgenic ALS mice and primary motoneuron cultures. Its mechanism of action and target cells in the spinal cord, however, are largely unknown. Using mixed motoneuron cultures, motoneuron-like NSC34 cells, and primary astroglia cultures as model systems, we here demonstrate that angiogenin is a neuronally secreted factor that is endocytosed by astroglia and mediates neuroprotection in paracrine. We show that wild-type angiogenin acts unidirectionally to induce RNA cleavage in astroglia, while the ALS-associated K40I mutant is also secreted and endocytosed, but fails to induce RNA cleavage. Angiogenin uptake into astroglia requires heparan sulfate proteoglycans, and engages clathrin-mediated endocytosis. We show that this uptake mechanism exists for mouse and human angiogenin, and delivers a functional RNase output. Moreover, we identify syndecan 4 as the angiogenin receptor mediating the selective uptake of angiogenin into astroglia. Our data provide new insights into the paracrine activities of angiogenin in the nervous system, and further highlight the critical role of non-neuronal cells in the pathogenesis of ALS.

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Nuclear translocation of angiogenin in proliferatingendothelial cells is essential to its angiogenic activity.

Cited by 245 publications

References 50 publications

Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E

Differential expression of vascular endothelial growth factor mRNA vs protein isoform expression in human breast cancer and relationship to eIF-4E

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

Motoneurons Secrete Angiogenin to Induce RNA Cleavage in Astroglia

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