Replacement of residues 8-22 of angiogenin with 7-21 of RNase A selectively affects protein synthesis inhibition and angiogenesis

Bond, Michael D.; Vallée, Bert L.

doi:10.1021/bi00465a028

Cited by 22 publications

(15 citation statements)

References 32 publications

(47 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Nonetheless, our results show substantial (5-8-fold) activity losses for K17I and K17E. A previous study (49) demonstrated that replacement of ANG residues 8-22 by RNase A residues 7-21 (thus replacing Lys17 by a Ser, along with many other changes) markedly decreases the potency of ANG in inhibiting cell-free protein synthesis, an activity that has been attributed to the action of ANG on rRNA in intact ribosomes (50). Lys17 may be part of a peripheral recognition site for rRNA, and since the natural substrate of ANG is not yet known, it is possible that Lys17 is also involved in binding this substrate.…”

Section: Discussionsupporting

confidence: 45%

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

et al. 2007

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionsupporting

confidence: 45%

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

et al. 2007

View full text Add to dashboard Cite

show abstract

“…Other regions that differ from the RNases include residues 5 -11 and 16-21, suggesting that the N-terminal region of angiogenin may also have a unique functional role. However, mutagenesis of angiogenin by replacing residues 8-22 with those of 7 -21 of RNase A did not affect its enzymatic activity, but did increase its angiogenic potency as well as its capacity to inhibit cell free protein synthesis [16].…”

Section: Properties Of Angiogeninmentioning

confidence: 90%

Organogenesis and angiogenin

Vallée

Riordan

1997

CMLS, Cell. mol. life sci.

View full text Add to dashboard Cite

Our search for an angiogenesis-inducing factor in culture medium conditioned by human colon adenocarcinoma cells (HT-29) was inspired by the 'organizer' hypothesis originally postulated by Spemann. It led us to the isolation of angiogenin, a 14 kD protein homologous to pancreatic ribonuclease and one of the most potent stimulators of blood vessel formation known. This review summarizes the properties of angiogenin, its enzymatic and three-dimensional relationship to ribonuclease A (RNase A), those aspects of its structure that are critical for its biological function, and the therapeutic potential of angiogenin inhibition. Despite having the same arrangement of catalytic residues as RNase A, angiogenin has very low enzymatic activity. It lacks one of the four disulphide loops of RNase A; instead, the corresponding residues form part of a cell binding region. Both the catalytic activity and cell binding site are essential for angiogenesis. Angiogenin binds to cell-surface actin in confluent endothelial cells and to an as yet uncharacterized receptor on proliferating cells. Internalization and translocation to the nucleolus are also required for activity. Inhibitors of angiogenin can block angiogenesis in vitro and prevent tumour growth in vivo. Thus, a noncytotoxic neutralizing monoclonal antibody prevents the establishment of HT-29 human tumour xenografts in up to 65% of treated athymic mice. In those tumours that develop, the number of vascular elements is reduced. Actin also prevents the establishment of tumours while exhibiting no toxic effects at daily doses > 50 times the molar amount of circulating mouse angiogenin. These antagonists also inhibit the appearance of tumours derived from two other human tumour cell lines. Inhibition of the action of angiogenin may prove to be an effective therapeutic approach for the treatment of malignant disease.

show abstract

“…A variety of studies, summarized in a previous review [9], show these regions to be of importance in what are postulated to be subaspects of angiogenic function. These are inhibition of cell-free protein synthesis [64] associated with region 1, nuclear translocation [54] with part of region 2, angiogenesis and the actin-binding site [5,65,66] partly with region 3, and inhibition of degranulation of polymorphonuclear leukocytes [67] with region 4. The underlying RNase activity is reflected by conservation of the catalytic residues His-13, Lys-40 and His-114, and of active site residues such as the RNase-1 signature region -the latter part of region 2.…”

Section: Multi-author Review Articlementioning

confidence: 99%

The angiogenins

Strydom¹

1998

Cellular and Molecular Life Sciences (CMLS)

149

125

View full text Add to dashboard Cite

The angiogenic and other biological functions of the angiogenins, members of the pancreatic RNase superfamily of proteins, are reviewed in the context of their primary and tertiary structures. The ribonucleolytic activity and interactions with the placental ribonuclease inhibitor have seen much study in the last few years. The mechanism of the angiogenic activity of angiogenin has recently been postulated as involving multiple interactions with other proteins through specific regions on the molecular surface of angiogenin. These molecular partners include heparin, plasminogen, elastase, angiostatin, actin and most importantly a 170-kilodalton receptor on subconfluent endothelial cells. The existence of the latter receptor was established in conjunction with a mitogenic activity of angiogenin on subconfluent cells. The levels of angiogenin in various physiological and disease states are summarized, including various studies on pregnancy and angiogenin. Correlations are seen between states of enhanced angiogenesis and angiogenin levels. An overview of the relationship of angiogenin and the other RNases of the superfamily showed that their genes all are in relative close proximity on human chromosome 14. Examination of the many expressed sequence tags published in the public databanks, for angiogenin and the other RNases, revealed that angiogenin and RNase-4 (the most evolutionarily conserved RNase), share various identical 5'-untranslated regions on their sets of messenger RNAs, suggesting that their genes are in very close proximity on chromosome 14 and that they are products of differential splicing. This in turn suggests that, in both humans and mice, expression of these two proteins is under identical control, with obvious implications for their biological activities. The evolutionary history of the angiogenins is examined briefly on the basis of the protein sequences of the human, rabbit, pig, two bovine and four mouse angiogenins, and two mouse angiogenin pseudogene sequences. The discrepancy between the conventional requirement for conservatism in structure to allow multimolecule interactions, and the actual fast-changing sequence of the angiogenins, in concert with the wide-ranging activity even in birds, of human angiogenin, is discussed.

show abstract

Replacement of residues 8-22 of angiogenin with 7-21 of RNase A selectively affects protein synthesis inhibition and angiogenesis

Cited by 22 publications

References 32 publications

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

Organogenesis and angiogenin

The angiogenins

Contact Info

Product

Resources

About