Angiogenin: Difference between revisions

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{{Distinguish|angiopoietin}}
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{{Infobox_gene}}
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'''Angiogenin''' (Ang) also known as '''ribonuclease 5''' is a small 123 amino acid [[protein]] that in humans is encoded by the ''ANG'' [[gene]].<ref name="Mechanisms of Ang">{{cite journal | vauthors=Gao X, Xu Z | title=Mechanisms of action of angiogenin | journal=Acta Biochimica et Biophysica Sinica | year=2008 | volume= 40 | issue= 7 | pages= 619–624 | pmid=18604453 | doi=10.1111/j.1745-7270.2008.00442.x}}</ref> Angiogenin is a potent stimulator of new blood vessels through the process of [[angiogenesis]]. Ang hydrolyzes cellular [[RNA]], resulting in modulated levels of protein synthesis and interacts with [[DNA]] causing a promoter-like increase in the expression of [[rRNA]].<ref name = "Ang Review">{{cite journal | author= Tello-Montoliu A | author2= Patel J.V. | author3= Lip G.Y.H. | title =Angiogenin: a review of the pathophysiology and potential clinical applications | journal=Journal of Thrombosis and Haemostasis | year= 2006 | volume= 4 | issue= 9 | pages= 1864–74 | DOI=10.1111/j.1538-7836.2006.01995.x}}</ref><ref name="ABE">{{ cite journal | vauthors=Xu Z, Tsuji T, Riordan J, Hu G | title=Identification and characterization of an angiogenin-binding DNA sequence that stimulate luciferase reporter gene expression | journal=Biochemistry | year= 2003 | volume= 42 | issue= 1 | pages= 121–128 | doi=10.1021/bi020465x}}</ref> Ang is associated with cancer and neurological disease through [[angiogenesis]] and through activating gene expression that suppresses [[apoptosis]].<ref name= "Ang Review"/><ref name= "Ang and Apoptosis">{{cite journal | vauthors=Li S, Yu W, Hu GF | title= Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner | journal=Journal of Cellular Physiology | year= 2012 | volume= 227 | issue= 4 | doi=10.1002/jcp.22881 | pages=1639–1644 | pmid=21678416 | pmc=3206144}}</ref><ref name="Ang and Parkinson's">{{cite journal | vauthors=Steidinger TU, Standaert DG, Yacoubian TA | title=A neuroprotective role for angiogenin in models of Parkinson’s disease | journal=Journal of Neurochemistry | year= 2011 | volume= 116 | issue= 3 | pages= 334–341 | doi=10.1111/j.1471-4159.2010.07112.x}}</ref>
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| update_citations = yes
== Function ==
}}
 
<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
Angiogenin is a key protein implicated in [[angiogenesis]] in normal and tumor growth. Angiogenin interacts with [[endothelial]] and [[smooth muscle]] cells resulting in cell migration, invasion, proliferation and formation of tubular structures.<ref name="Mechanisms of Ang"/> Ang binds to [[actin]] of both smooth muscle and [[endothelial]] cells to form complexes that activate [[proteolytic]] cascades which upregulate the production of [[proteases]] and [[plasmin]] that degrade the [[laminin]] and [[fibronectin]] layers of the [[basement membrane]].<ref name= "Ang Review"/> Degradation of the [[basement membrane]] and [[extracellular matrix]] allows the endothelial cells to penetrate and migrate into the [[Smooth muscle tissue|perivascular]] tissue.<ref name="Mechanisms of Ang"/> Signal transduction pathways activated by Ang interactions at the cellular membrane of endothelial cells produce [[Extracellular signal-regulated kinases|extracellular signal-related kinase1/2]] (ERK1/2) and protein kinase B/[[Akt]].<ref name="Mechanisms of Ang"/> Activation of these proteins leads to invasion of the basement membrane and [[cell proliferation]] associated with further [[angiogenesis]]. The most important step in the angiogenesis process is the translocation of Ang to the cell nucleus. Once Ang has been translocated to the nucleus, it enhances [[rRNA]] transcription by binding to the CT-rich (CTCTCTCTCTCTCTCTCCCTC) angiogenin binding element (ABE) within the upstream intergenic region of [[Ribosomal DNA|rDNA]], which subsequently activates other angiogenic factors that induce [[angiogenesis]].<ref name="Mechanisms of Ang"/><ref name="ABE"/><ref name="Stress tRNA">{{cite journal| vauthors=Fu H, Feng J, Liu Q, Sun F, Tie Y, Zhu J, Xing R, Sun Z, Zheng X | title=Stress induces tRNA cleavage by angiogenin in mammalian cells | journal=FEBS Letters | year=2008 | volume= 583 | issue= 2 | pages=437–42 | pmid=19114040 | doi=10.1016/j.febslet.2008.12.043}}</ref>
{{GNF_Protein_box
 
| image = PBB_Protein_ANG_image.jpg
However, angiogenin is unique among the many proteins that are involved in angiogenesis in that it is also an [[enzyme]] with an [[amino acid]] sequence 33% identical to that of [[bovine]] [[pancreatic]] [[ribonuclease]] (RNase) A.<ref name="Mechanisms of Ang"/> Ang has the same general [[catalytic]] properties as RNase A, it cleaves preferentially on the 3' side of [[pyrimidines]] and follows a transphosphorylation/[[hydrolysis]] mechanism.<ref name="Raines">{{cite journal | vauthors=Leland PA, Staniszewski KE, Park C, Keleman BR, Raines RT | title=The ribonucleolytic activity of angiogenin | journal=Biochemistry | year= 2002 | volume= 41 | issue= 4 | doi=10.1021/bi0117899 | pages=1343–1350}}</ref> Although angiogenin contains many of the same catalytic residues as [[RNase A]], it cleaves standard RNA substrates 10<sup>5</sup>–10<sup>6</sup> times less efficiently than does [[RNase A]].<ref name="Raines"/> The reason for this inefficiency is due to the 117 residue consisting of a [[glutamine]], which blocks the catalytic site.<ref name="Shapiro">{{cite journal | vauthors=Russo N, Shapiro R, Acharya KR, Riordan JF, Vallee BL  | title=Role of glutamine-117 in the ribonucleolytic activity of human angiogenin | journal=Biochemistry | year= 1994 | volume= 91 | issue= 9 | pages= 2920–2924 | doi=10.1073/pnas.91.8.2920}}</ref> Removal of this residue through mutation increases the ribonuclease activity between 11 and 30 fold.<ref name="Shapiro"/> Despite this apparent weakness, the enzymatic activity of Ang appears to be essential for biological activity: replacements of important [[catalytic]] site residues ([[Histidine]]13 and [[Histidine]] 114) invariably diminish both the [[ribonuclease]] activity toward [[tRNA]] by 10,000 fold and almost abolishes [[angiogenesis]] activities completely.<ref name="Shapiro2">{{cite journal | vauthors=Shapiro R, Valle BL | title=Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis | journal=Biochemistry | year=1989 | volume= 28 | issue= 18 | pages=7401–7408 | doi=10.1021/bi00444a038 | pmid=2479414}}</ref>
| image_source = Ribonuclease inhibitor-angiogenin complex. From {{PDB|1a4y}}
 
| PDB = {{PDB2|1a4y}}, {{PDB2|1ang}}, {{PDB2|1awz}}, {{PDB2|1b1e}}, {{PDB2|1b1i}}, {{PDB2|1b1j}}, {{PDB2|1h0d}}, {{PDB2|1h52}}, {{PDB2|1h53}}, {{PDB2|1hby}}, {{PDB2|1k58}}, {{PDB2|1k59}}, {{PDB2|1k5a}}, {{PDB2|1k5b}}, {{PDB2|1un3}}, {{PDB2|1un4}}, {{PDB2|1un5}}, {{PDB2|2ang}}
== Disease ==
| Name = Angiogenin, ribonuclease, RNase A family, 5
 
| HGNCid = 483
=== Cancer ===
| Symbol = ANG
 
| AltSymbols =; MGC71966; RNASE4; RNASE5
Ang has a prominent role in the pathology of [[cancer]] due to its functions in [[angiogenesis]] and cell survival. Since Ang possesses angiogenic activity, it makes Ang a possible candidate in therapeutic treatments of cancer. Studies of Ang and tumor relationships provide evidence for a connection between the two. The translocation of Ang to the nucleus causes an upregulation of transcriptional [[rRNA]], while knockdown strains of Ang cause downregulation.<ref name="Mechanisms of Ang"/> The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis.<ref name="Mechanisms of Ang"/><ref name="Stress RNA">{{ cite journal | vauthors=Li S, Hu G | title=Emerging role of angiogenin in stress response and cell survival under adverse conditions | journal=Journal of Cell Physiology | year=2012 | volume=227 | issue=7 | pages= 2822–6 | doi=10.1002/jcp.23051}}</ref> [[HeLa]] cells translocate Ang to the nucleus independent of cell density. In [[human umbilical vein endothelial cell]]s(HUVEC), translocation of Ang to the nucleus stops after cells reach a specific density, while in [[HeLa]] cells translocation continued past that point.<ref name="Hela">{{ cite journal | vauthors=Tsuji T, Sun Y, Kishimoto K, Olson K, Luo S, Hirukawa S, Hu G| title=Angiogenin is translocated to the nucleus of HeLa cells and is involved in ribosomal RNA transcription and cell proliferation | journal=Cancer Research | year= 2005 | volume= 65 | pages=1352–1360 | doi=10.1158/0008-5472.CAN-04-2058 | pmid=15735021}}</ref> Inhibition of Ang affects the ability of [[HeLa]] cells to proliferate, which proposes an effective target for possible therapies.
| OMIM = 105850
| ECnumber =
| Homologene = 74385
| MGIid = 88022
| Function = {{GNF_GO|id=GO:0003677 |text = DNA binding}} {{GNF_GO|id=GO:0003779 |text = actin binding}} {{GNF_GO|id=GO:0004519 |text = endonuclease activity}} {{GNF_GO|id=GO:0004522 |text = pancreatic ribonuclease activity}} {{GNF_GO|id=GO:0004540 |text = ribonuclease activity}} {{GNF_GO|id=GO:0005102 |text = receptor binding}} {{GNF_GO|id=GO:0005507 |text = copper ion binding}} {{GNF_GO|id=GO:0008201 |text = heparin binding}} {{GNF_GO|id=GO:0016787 |text = hydrolase activity}} {{GNF_GO|id=GO:0019843 |text = rRNA binding}}  
| Component = {{GNF_GO|id=GO:0005605 |text = basal lamina}} {{GNF_GO|id=GO:0005615 |text = extracellular space}} {{GNF_GO|id=GO:0005634 |text = nucleus}} {{GNF_GO|id=GO:0005730 |text = nucleolus}} {{GNF_GO|id=GO:0032311 |text = angiogenin-PRI complex}}
| Process = {{GNF_GO|id=GO:0001525 |text = angiogenesis}} {{GNF_GO|id=GO:0001541 |text = ovarian follicle development}} {{GNF_GO|id=GO:0001666 |text = response to hypoxia}} {{GNF_GO|id=GO:0001890 |text = placenta development}} {{GNF_GO|id=GO:0001938 |text = positive regulation of endothelial cell proliferation}} {{GNF_GO|id=GO:0006651 |text = diacylglycerol biosynthetic process}} {{GNF_GO|id=GO:0007154 |text = cell communication}} {{GNF_GO|id=GO:0007202 |text = phospholipase C activation}} {{GNF_GO|id=GO:0007275 |text = multicellular organismal development}} {{GNF_GO|id=GO:0009303 |text = rRNA transcription}} {{GNF_GO|id=GO:0017148 |text = negative regulation of protein biosynthetic process}} {{GNF_GO|id=GO:0030041 |text = actin filament polymerization}} {{GNF_GO|id=GO:0030154 |text = cell differentiation}} {{GNF_GO|id=GO:0032431 |text = activation of phospholipase A2}} {{GNF_GO|id=GO:0042592 |text = homeostatic process}} {{GNF_GO|id=GO:0048662 |text = negative regulation of smooth muscle cell proliferation}} {{GNF_GO|id=GO:0050714 |text = positive regulation of protein secretion}}  
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 283
    | Hs_Ensembl =
    | Hs_RefseqProtein = NP_001136
    | Hs_RefseqmRNA = NM_001145
    | Hs_GenLoc_db =
    | Hs_GenLoc_chr =
    | Hs_GenLoc_start =
    | Hs_GenLoc_end =
    | Hs_Uniprot =
    | Mm_EntrezGene = 11727
    | Mm_Ensembl = ENSMUSG00000072115
    | Mm_RefseqmRNA = NM_007447
    | Mm_RefseqProtein = NP_031473
    | Mm_GenLoc_db =
    | Mm_GenLoc_chr = 14
    | Mm_GenLoc_start = 50018364
    | Mm_GenLoc_end = 50023962
    | Mm_Uniprot = Q3TBG7
  }}
}}


'''Angiogenin''' (Ang) is a small [[polypeptide]] that is implicated in [[angiogenesis]] (formation of new blood vessels) in tumor growth . However, angiogenin is unique among the many proteins that are involved in angiogenesis in that it is also an [[enzyme]] with an [[amino acid]] sequence 33% identical to that of [[bovine]] [[pancreatic]] [[ribonuclease]] (RNase) A). Moreover, although Ang has the same general [[catalytic]] properties as RNase A - it cleaves preferentially on the 3' side of [[pyrimidines]] and follows a transphosphorylation/[[hydrolysis]] mechanism - its activity differs markedly both in magnitude and in specificity.
=== Neurodegenerative diseases ===


Although angiogenin contains counterparts for the key catalytic residues of bovine pancreatic RNase A, it cleaves standard RNase substrates 10<sup>5</sup> - 10<sup>6</sup> times less efficiently than does RNase A. Despite this apparent weakness, the enzymatic activity of Ang appears to be essential for biological activity: replacements of important active site residues
Due to the ability of Ang to protect [[motoneurons]] (MNs), causal links between Ang mutations and [[Amyotrophic lateral sclerosis]] (ALS) are likely. The angiogenic factors associated with Ang may protect the central nervous system and MNs directly.<ref name="Mechanisms of Ang"/> Experiments with wild type Ang found that it slows MN degeneration in mice that had developed ALS, providing evidence for further development of Ang protein therapy in ALS treatment.<ref name="Stress RNA"/> Angiogenin expression in Parkinson's disease is dramatically decreased in the presence of [[alpha-synuclein]] (α-syn) aggregations. Exogenous angiogenin applied to [[dopamine]]-producing cells leads to the [[phosphorylation]] of PKB/[[AKT]] and the activation of this complex inhibits cleavage of [[caspase 3]] and [[apoptosis]] when cells are exposed to a [[Parkinson's]]-like inducing substance.<ref name="PD">{{ cite journal | vauthors=Steidinger TU, Standaert DG, Yacoubian TA | title=A neuroprotective role for angiogenin in models of Parkinson’s disease | journal=Journal of Neurochemistry | year=2010 | volume=116 | issue=3 | pages=334–341 | doi=10.1111/j.1471-4159.2010.07112.x}}</ref>
invariably diminish [[ribonuclease]] and [[angiogenesis]] activities in parallel, and a substitution that increases [[enzymatic]] activity also enhances [[angiogenic]] potency.


Angiogenin may function as a [[tRNA]]-specific [[ribonuclease]] that binds to [[actin]] on the surface of [[endothelial]] cells; once bound, angiogenin is endocytosed and translocated to the [[Cell nucleus|nucleus]], thereby promoting the [[endothelial]] invasiveness necessary for [[blood vessel]] formation. Angiogenin induces [[vascularization]] of normal and [[malignant]] tissues, and abolishes protein synthesis by specifically hydrolyzing cellular tRNAs.
== Gene ==


[[Alternative splicing]] results in two transcript variants encoding the same protein. This gene and the gene that encodes ribonuclease, RNase A family, 4 share [[promoter]]s and 5' [[exon]]s. Each gene splices to a unique downstream exon that contains its complete coding region.<ref>{{cite web | title = Entrez Gene: ANG angiogenin, ribonuclease, RNase A family, 5| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=283| accessdate = }}</ref>
[[Alternative splicing]] results in two transcript variants encoding the same protein. This gene and the gene that encodes ribonuclease, [[Ribonuclease 4|RNase A family, 4]] share [[Promoter (biology)|promoter]]s and 5' [[exon]]s. Each gene splices to a unique downstream exon that contains its complete coding region.<ref name = "entrez">{{cite web | title = Entrez Gene: ANG angiogenin, ribonuclease, RNase A family, 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=283| accessdate = }}</ref>


==References==
==References==
{{reflist|2}}
{{reflist}}
 
==External links==
* {{UCSC gene info|ANG}}
* {{UCSC gene info|RNASE4}}
* {{UCSC gene info|AMOT}}
 
==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading  
{{PBB_Further_reading  
| citations =  
| citations =  
*{{cite journal  | author=Saxena SK, Rybak SM, Davey RT, ''et al.'' |title=Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily. |journal=J. Biol. Chem. |volume=267 |issue= 30 |pages= 21982-6 |year= 1992 |pmid= 1400510 |doi=  }}
*{{cite journal  | author=Saxena SK |title=Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily |journal=J. Biol. Chem. |volume=267 |issue= 30 |pages= 21982–6 |year= 1992 |pmid= 1400510 |doi=  | name-list-format=vanc | author2=Rybak SM  | author3=Davey RT  | display-authors=3  | last4=Youle  | first4=RJ  | last5=Ackerman  | first5=EJ  }}
*{{cite journal  | author=Weremowicz S, Fox EA, Morton CC, Vallee BL |title=Localization of the human angiogenin gene to chromosome band 14q11, proximal to the T cell receptor alpha/delta locus. |journal=Am. J. Hum. Genet. |volume=47 |issue= 6 |pages= 973-81 |year= 1990 |pmid= 1978563 |doi=  }}
*{{cite journal  | vauthors=Weremowicz S, Fox EA, Morton CC, Vallee BL |title=The placental ribonuclease inhibitor (RNH) gene is located on chromosome subband 11p15.5 |journal=Genomics |volume=8 |issue= 4 |pages= 717–21 |year= 1991 |pmid= 2276743 |doi=10.1016/0888-7543(90)90260-2 }}
*{{cite journal  | author=Weremowicz S, Fox EA, Morton CC, Vallee BL |title=The placental ribonuclease inhibitor (RNH) gene is located on chromosome subband 11p15.5. |journal=Genomics |volume=8 |issue= 4 |pages= 717-21 |year= 1991 |pmid= 2276743 |doi=  }}
*{{cite journal  | vauthors=Shapiro R, Riordan JF, Vallee BL |title=Characteristic ribonucleolytic activity of human angiogenin |journal=Biochemistry |volume=25 |issue= 12 |pages= 3527–32 |year= 1986 |pmid= 2424496 |doi=10.1021/bi00360a008 }}
*{{cite journal  | author=Shapiro R, Riordan JF, Vallee BL |title=Characteristic ribonucleolytic activity of human angiogenin. |journal=Biochemistry |volume=25 |issue= 12 |pages= 3527-32 |year= 1986 |pmid= 2424496 |doi=  }}
*{{cite journal  | vauthors=Weiner HL, Weiner LH, Swain JL |title=Tissue distribution and developmental expression of the messenger RNA encoding angiogenin |journal=Science |volume=237 |issue= 4812 |pages= 280–2 |year= 1987 |pmid= 2440105 |doi=10.1126/science.2440105 }}
*{{cite journal  | author=Weiner HL, Weiner LH, Swain JL |title=Tissue distribution and developmental expression of the messenger RNA encoding angiogenin. |journal=Science |volume=237 |issue= 4812 |pages= 280-2 |year= 1987 |pmid= 2440105 |doi=  }}
*{{cite journal  | vauthors=Bicknell R, Vallee BL |title=Angiogenin activates endothelial cell phospholipase C |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 16 |pages= 5961–5 |year= 1988 |pmid= 2457905 |doi=10.1073/pnas.85.16.5961  | pmc=281885  }}
*{{cite journal  | author=Bicknell R, Vallee BL |title=Angiogenin activates endothelial cell phospholipase C. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=85 |issue= 16 |pages= 5961-5 |year= 1988 |pmid= 2457905 |doi= }}
*{{cite journal  | vauthors=Shapiro R, Vallee BL |title=Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis |journal=Biochemistry |volume=28 |issue= 18 |pages= 7401–8 |year= 1990 |pmid= 2479414 |doi=10.1021/bi00444a038 }}
*{{cite journal  | author=Shapiro R, Vallee BL |title=Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis. |journal=Biochemistry |volume=28 |issue= 18 |pages= 7401-8 |year= 1990 |pmid= 2479414 |doi=  }}
*{{cite journal  | vauthors=Bicknell R, Vallee BL |title=Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2 |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue= 5 |pages= 1573–7 |year= 1989 |pmid= 2646638 |doi=10.1073/pnas.86.5.1573  | pmc=286740  }}
*{{cite journal  | author=Bicknell R, Vallee BL |title=Angiogenin stimulates endothelial cell prostacyclin secretion by activation of phospholipase A2. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=86 |issue= 5 |pages= 1573-7 |year= 1989 |pmid= 2646638 |doi= }}
*{{cite journal  | vauthors=Lee FS, Vallee BL |title=Characterization of ribonucleolytic activity of angiogenin towards tRNA |journal=Biochem. Biophys. Res. Commun. |volume=161 |issue= 1 |pages= 121–6 |year= 1989 |pmid= 2730651 |doi=10.1016/0006-291X(89)91569-6 }}
*{{cite journal  | author=Lee FS, Vallee BL |title=Characterization of ribonucleolytic activity of angiogenin towards tRNA. |journal=Biochem. Biophys. Res. Commun. |volume=161 |issue= 1 |pages= 121-6 |year= 1989 |pmid= 2730651 |doi=  }}
*{{cite journal  | vauthors=Lee FS, Vallee BL |title=Binding of placental ribonuclease inhibitor to the active site of angiogenin |journal=Biochemistry |volume=28 |issue= 8 |pages= 3556–61 |year= 1989 |pmid= 2742853 |doi=10.1021/bi00434a061 }}
*{{cite journal  | author=Lee FS, Vallee BL |title=Binding of placental ribonuclease inhibitor to the active site of angiogenin. |journal=Biochemistry |volume=28 |issue= 8 |pages= 3556-61 |year= 1989 |pmid= 2742853 |doi=  }}
*{{cite journal  | author=Strydom DJ |title=Amino acid sequence of human tumor derived angiogenin |journal=Biochemistry |volume=24 |issue= 20 |pages= 5486–94 |year= 1986 |pmid= 2866794 |doi=10.1021/bi00341a031 | name-list-format=vanc | author2=Fett JW  | author3=Lobb RR  | display-authors=3  | last4=Alderman  | first4=Edward M.  | last5=Bethune  | first5=J. Lemuel  | last6=Riordan  | first6=James F.  | last7=Vallee  | first7=Bert L. }}
*{{cite journal  | author=Strydom DJ, Fett JW, Lobb RR, ''et al.'' |title=Amino acid sequence of human tumor derived angiogenin. |journal=Biochemistry |volume=24 |issue= 20 |pages= 5486-94 |year= 1986 |pmid= 2866794 |doi= }}
*{{cite journal  | author=Kurachi K |title=Sequence of the cDNA and gene for angiogenin, a human angiogenesis factor |journal=Biochemistry |volume=24 |issue= 20 |pages= 5494–9 |year= 1986 |pmid= 2866795 |doi=10.1021/bi00341a032 | name-list-format=vanc | author2=Davie EW  | author3=Strydom DJ  | display-authors=3  | last4=Riordan  | first4=James F.  | last5=Vallee  | first5=Bert L. }}
*{{cite journal | author=Kurachi K, Davie EW, Strydom DJ, ''et al.'' |title=Sequence of the cDNA and gene for angiogenin, a human angiogenesis factor. |journal=Biochemistry |volume=24 |issue= 20 |pages= 5494-9 |year= 1986 |pmid= 2866795 |doi=  }}
*{{cite journal  | vauthors=Shapiro R, Vallee BL |title=Human placental ribonuclease inhibitor abolishes both angiogenic and ribonucleolytic activities of angiogenin |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 8 |pages= 2238–41 |year= 1987 |pmid= 3470787 |doi=10.1073/pnas.84.8.2238  | pmc=304624  }}
*{{cite journal  | author=Shapiro R, Vallee BL |title=Human placental ribonuclease inhibitor abolishes both angiogenic and ribonucleolytic activities of angiogenin. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 8 |pages= 2238-41 |year= 1987 |pmid= 3470787 |doi= }}
*{{cite journal  | vauthors=Rybak SM, Fett JW, Yao QZ, Vallee BL |title=Angiogenin mRNA in human tumor and normal cells |journal=Biochem. Biophys. Res. Commun. |volume=146 |issue= 3 |pages= 1240–8 |year= 1987 |pmid= 3619929 |doi=10.1016/0006-291X(87)90781-9 }}
*{{cite journal | author=Rybak SM, Fett JW, Yao QZ, Vallee BL |title=Angiogenin mRNA in human tumor and normal cells. |journal=Biochem. Biophys. Res. Commun. |volume=146 |issue= 3 |pages= 1240-8 |year= 1987 |pmid= 3619929 |doi=  }}
*{{cite journal  | vauthors=Shapiro R, Strydom DJ, Olson KA, Vallee BL |title=Isolation of angiogenin from normal human plasma |journal=Biochemistry |volume=26 |issue= 16 |pages= 5141–6 |year= 1987 |pmid= 3663649 |doi=10.1021/bi00390a037  }}
*{{cite journal  | author=Shapiro R, Strydom DJ, Olson KA, Vallee BL |title=Isolation of angiogenin from normal human plasma. |journal=Biochemistry |volume=26 |issue= 16 |pages= 5141-6 |year= 1987 |pmid= 3663649 |doi= }}
*{{cite journal  | author=Hu GF |title=Actin is a binding protein for angiogenin |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 4 |pages= 1217–21 |year= 1993 |pmid= 7679494 |doi=10.1073/pnas.90.4.1217  | pmc=45843 | name-list-format=vanc | author2=Strydom DJ  | author3=Fett JW  | display-authors=3  | last4=Riordan  | first4=JF  | last5=Vallee  | first5=BL  }}
*{{cite journal  | author=Hu GF, Strydom DJ, Fett JW, ''et al.'' |title=Actin is a binding protein for angiogenin. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=90 |issue= 4 |pages= 1217-21 |year= 1993 |pmid= 7679494 |doi=  }}
*{{cite journal  | vauthors=Moroianu J, Riordan JF |title=Identification of the nucleolar targeting signal of human angiogenin |journal=Biochem. Biophys. Res. Commun. |volume=203 |issue= 3 |pages= 1765–72 |year= 1994 |pmid= 7945327 |doi= 10.1006/bbrc.1994.2391 }}
*{{cite journal  | author=Moroianu J, Riordan JF |title=Identification of the nucleolar targeting signal of human angiogenin. |journal=Biochem. Biophys. Res. Commun. |volume=203 |issue= 3 |pages= 1765-72 |year= 1994 |pmid= 7945327 |doi= 10.1006/bbrc.1994.2391 }}
*{{cite journal  | vauthors=Moroianu J, Riordan JF |title=Nuclear translocation of angiogenin in proliferating endothelial cells is essential to its angiogenic activity |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 5 |pages= 1677–81 |year= 1994 |pmid= 8127865 |doi=10.1073/pnas.91.5.1677  | pmc=43226  }}
*{{cite journal  | author=Moroianu J, Riordan JF |title=Nuclear translocation of angiogenin in proliferating endothelial cells is essential to its angiogenic activity. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 5 |pages= 1677-81 |year= 1994 |pmid= 8127865 |doi=  }}
*{{cite journal  | author=Acharya KR |title=Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 8 |pages= 2915–9 |year= 1994 |pmid= 8159679 |doi=10.1073/pnas.91.8.2915  | pmc=43485  | name-list-format=vanc | author2=Shapiro R  | author3=Allen SC  | display-authors=3  | last4=Riordan  | first4=JF  | last5=Vallee  | first5=BL  }}
*{{cite journal  | author=Acharya KR, Shapiro R, Allen SC, ''et al.'' |title=Crystal structure of human angiogenin reveals the structural basis for its functional divergence from ribonuclease. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=91 |issue= 8 |pages= 2915-9 |year= 1994 |pmid= 8159679 |doi=  }}
*{{cite journal  | vauthors=Hu GF, Riordan JF, Vallee BL |title=A putative angiogenin receptor in angiogenin-responsive human endothelial cells |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 6 |pages= 2204–9 |year= 1997 |pmid= 9122172 |doi=10.1073/pnas.94.6.2204  | pmc=20065 }}
*{{cite journal  | author=Hu GF, Riordan JF, Vallee BL |title=A putative angiogenin receptor in angiogenin-responsive human endothelial cells. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=94 |issue= 6 |pages= 2204-9 |year= 1997 |pmid= 9122172 |doi=  }}
}}
}}
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[[Category:Biomolecules]]
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{{Angiogenic proteins}}
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[[uk:Ангіогенін]]
[[Category:Biomolecules]]
[[Category:EC 3.1.27]]

Revision as of 01:32, 27 October 2017

Not to be confused with angiopoietin.
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Angiogenin (Ang) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene.[1] Angiogenin is a potent stimulator of new blood vessels through the process of angiogenesis. Ang hydrolyzes cellular RNA, resulting in modulated levels of protein synthesis and interacts with DNA causing a promoter-like increase in the expression of rRNA.[2][3] Ang is associated with cancer and neurological disease through angiogenesis and through activating gene expression that suppresses apoptosis.[2][4][5]

Function

Angiogenin is a key protein implicated in angiogenesis in normal and tumor growth. Angiogenin interacts with endothelial and smooth muscle cells resulting in cell migration, invasion, proliferation and formation of tubular structures.[1] Ang binds to actin of both smooth muscle and endothelial cells to form complexes that activate proteolytic cascades which upregulate the production of proteases and plasmin that degrade the laminin and fibronectin layers of the basement membrane.[2] Degradation of the basement membrane and extracellular matrix allows the endothelial cells to penetrate and migrate into the perivascular tissue.[1] Signal transduction pathways activated by Ang interactions at the cellular membrane of endothelial cells produce extracellular signal-related kinase1/2 (ERK1/2) and protein kinase B/Akt.[1] Activation of these proteins leads to invasion of the basement membrane and cell proliferation associated with further angiogenesis. The most important step in the angiogenesis process is the translocation of Ang to the cell nucleus. Once Ang has been translocated to the nucleus, it enhances rRNA transcription by binding to the CT-rich (CTCTCTCTCTCTCTCTCCCTC) angiogenin binding element (ABE) within the upstream intergenic region of rDNA, which subsequently activates other angiogenic factors that induce angiogenesis.[1][3][6]

However, angiogenin is unique among the many proteins that are involved in angiogenesis in that it is also an enzyme with an amino acid sequence 33% identical to that of bovine pancreatic ribonuclease (RNase) A.[1] Ang has the same general catalytic properties as RNase A, it cleaves preferentially on the 3' side of pyrimidines and follows a transphosphorylation/hydrolysis mechanism.[7] Although angiogenin contains many of the same catalytic residues as RNase A, it cleaves standard RNA substrates 105–106 times less efficiently than does RNase A.[7] The reason for this inefficiency is due to the 117 residue consisting of a glutamine, which blocks the catalytic site.[8] Removal of this residue through mutation increases the ribonuclease activity between 11 and 30 fold.[8] Despite this apparent weakness, the enzymatic activity of Ang appears to be essential for biological activity: replacements of important catalytic site residues (Histidine13 and Histidine 114) invariably diminish both the ribonuclease activity toward tRNA by 10,000 fold and almost abolishes angiogenesis activities completely.[9]

Disease

Cancer

Ang has a prominent role in the pathology of cancer due to its functions in angiogenesis and cell survival. Since Ang possesses angiogenic activity, it makes Ang a possible candidate in therapeutic treatments of cancer. Studies of Ang and tumor relationships provide evidence for a connection between the two. The translocation of Ang to the nucleus causes an upregulation of transcriptional rRNA, while knockdown strains of Ang cause downregulation.[1] The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis.[1][10] HeLa cells translocate Ang to the nucleus independent of cell density. In human umbilical vein endothelial cells(HUVEC), translocation of Ang to the nucleus stops after cells reach a specific density, while in HeLa cells translocation continued past that point.[11] Inhibition of Ang affects the ability of HeLa cells to proliferate, which proposes an effective target for possible therapies.

Neurodegenerative diseases

Due to the ability of Ang to protect motoneurons (MNs), causal links between Ang mutations and Amyotrophic lateral sclerosis (ALS) are likely. The angiogenic factors associated with Ang may protect the central nervous system and MNs directly.[1] Experiments with wild type Ang found that it slows MN degeneration in mice that had developed ALS, providing evidence for further development of Ang protein therapy in ALS treatment.[10] Angiogenin expression in Parkinson's disease is dramatically decreased in the presence of alpha-synuclein (α-syn) aggregations. Exogenous angiogenin applied to dopamine-producing cells leads to the phosphorylation of PKB/AKT and the activation of this complex inhibits cleavage of caspase 3 and apoptosis when cells are exposed to a Parkinson's-like inducing substance.[12]

Gene

Alternative splicing results in two transcript variants encoding the same protein. This gene and the gene that encodes ribonuclease, RNase A family, 4 share promoters and 5' exons. Each gene splices to a unique downstream exon that contains its complete coding region.[13]

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 Gao X, Xu Z (2008). "Mechanisms of action of angiogenin". Acta Biochimica et Biophysica Sinica. 40 (7): 619–624. doi:10.1111/j.1745-7270.2008.00442.x. PMID 18604453.
  2. ↑ 2.0 2.1 2.2 Tello-Montoliu A; Patel J.V.; Lip G.Y.H. (2006). "Angiogenin: a review of the pathophysiology and potential clinical applications". Journal of Thrombosis and Haemostasis. 4 (9): 1864–74. doi:10.1111/j.1538-7836.2006.01995.x.
  3. ↑ 3.0 3.1 Xu Z, Tsuji T, Riordan J, Hu G (2003). "Identification and characterization of an angiogenin-binding DNA sequence that stimulate luciferase reporter gene expression". Biochemistry. 42 (1): 121–128. doi:10.1021/bi020465x.
  4. ↑ Li S, Yu W, Hu GF (2012). "Angiogenin inhibits nuclear translocation of apoptosis inducing factor in a Bcl-2-dependent manner". Journal of Cellular Physiology. 227 (4): 1639–1644. doi:10.1002/jcp.22881. PMC 3206144. PMID 21678416.
  5. ↑ Steidinger TU, Standaert DG, Yacoubian TA (2011). "A neuroprotective role for angiogenin in models of Parkinson's disease". Journal of Neurochemistry. 116 (3): 334–341. doi:10.1111/j.1471-4159.2010.07112.x.
  6. ↑ Fu H, Feng J, Liu Q, Sun F, Tie Y, Zhu J, Xing R, Sun Z, Zheng X (2008). "Stress induces tRNA cleavage by angiogenin in mammalian cells". FEBS Letters. 583 (2): 437–42. doi:10.1016/j.febslet.2008.12.043. PMID 19114040.
  7. ↑ 7.0 7.1 Leland PA, Staniszewski KE, Park C, Keleman BR, Raines RT (2002). "The ribonucleolytic activity of angiogenin". Biochemistry. 41 (4): 1343–1350. doi:10.1021/bi0117899.
  8. ↑ 8.0 8.1 Russo N, Shapiro R, Acharya KR, Riordan JF, Vallee BL (1994). "Role of glutamine-117 in the ribonucleolytic activity of human angiogenin". Biochemistry. 91 (9): 2920–2924. doi:10.1073/pnas.91.8.2920.
  9. ↑ Shapiro R, Valle BL (1989). "Site-directed mutagenesis of histidine-13 and histidine-114 of human angiogenin. Alanine derivatives inhibit angiogenin-induced angiogenesis". Biochemistry. 28 (18): 7401–7408. doi:10.1021/bi00444a038. PMID 2479414.
  10. ↑ 10.0 10.1 Li S, Hu G (2012). "Emerging role of angiogenin in stress response and cell survival under adverse conditions". Journal of Cell Physiology. 227 (7): 2822–6. doi:10.1002/jcp.23051.
  11. ↑ Tsuji T, Sun Y, Kishimoto K, Olson K, Luo S, Hirukawa S, Hu G (2005). "Angiogenin is translocated to the nucleus of HeLa cells and is involved in ribosomal RNA transcription and cell proliferation". Cancer Research. 65: 1352–1360. doi:10.1158/0008-5472.CAN-04-2058. PMID 15735021.
  12. ↑ Steidinger TU, Standaert DG, Yacoubian TA (2010). "A neuroprotective role for angiogenin in models of Parkinson's disease". Journal of Neurochemistry. 116 (3): 334–341. doi:10.1111/j.1471-4159.2010.07112.x.
  13. ↑ "Entrez Gene: ANG angiogenin, ribonuclease, RNase A family, 5".

External links

Further reading

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