Angiogenin

Last updated
ANG
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ANG , ALS9, HEL168, RAA1, RNASE4, RNASE5, angiogenin, ribonuclease, RNase A family, 5, angiogenin
External IDs OMIM: 105850 MGI: 88022 HomoloGene: 74385 GeneCards: ANG
Orthologs
SpeciesHumanMouse
Entrez

283

11727

Ensembl

ENSG00000214274

ENSMUSG00000072115

UniProt

P03950

P21570

RefSeq (mRNA)

NM_001145
NM_001097577

NM_001161731
NM_007447

RefSeq (protein)

NP_001091046
NP_001136

NP_001155203
NP_031473

Location (UCSC) Chr 14: 20.68 – 20.7 Mb Chr 14: 51.33 – 51.34 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Angiogenin (ANG) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene. [5] 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. [6] [7] Ang is associated with cancer and neurological disease through angiogenesis and through activating gene expression that suppresses apoptosis. [6] [8] [9]

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. [5] 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. [6] Degradation of the basement membrane and extracellular matrix allows the endothelial cells to penetrate and migrate into the perivascular tissue. [5] 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. [5] 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. [5] [7] [10]

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). [5] 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. [11] Although angiogenin contains many of the same catalytic residues as RNase A, it cleaves standard RNA substrates 105–106 times less efficiently than RNase A. [11] The reason for this inefficiency is due to the 117 residue consisting of a glutamine, which blocks the catalytic site. [12] Removal of this residue through mutation increases the ribonuclease activity between 11 and 30 fold. [12] 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. [13]

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. [5] The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis. [5] [14] HeLa cells translocate Ang to the nucleus independent of cell density. In human umbilical vein endothelial cells (HUVECs), translocation of Ang to the nucleus stops after cells reach a specific density, while in HeLa cells translocation continued past that point. [15] 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. [5] 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. [14] 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. [9]

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. [16]

Related Research Articles

<span class="mw-page-title-main">Ribonuclease</span> Class of enzyme that catalyzes the degradation of RNA

Ribonuclease is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within the EC 2.7 and 3.1 classes of enzymes.

<span class="mw-page-title-main">Ribonuclease H</span> Enzyme family

Ribonuclease H is a family of non-sequence-specific endonuclease enzymes that catalyze the cleavage of RNA in an RNA/DNA substrate via a hydrolytic mechanism. Members of the RNase H family can be found in nearly all organisms, from bacteria to archaea to eukaryotes.

<span class="mw-page-title-main">Endostatin</span>

Endostatin is a naturally occurring, 20-kDa C-terminal fragment derived from type XVIII collagen. It is reported to serve as an anti-angiogenic agent, similar to angiostatin and thrombospondin.

<span class="mw-page-title-main">Ribonuclease P</span> Class of enzymes

Ribonuclease P is a type of ribonuclease which cleaves RNA. RNase P is unique from other RNases in that it is a ribozyme – a ribonucleic acid that acts as a catalyst in the same way that a protein-based enzyme would. Its function is to cleave off an extra, or precursor, sequence of RNA on tRNA molecules. Further, RNase P is one of two known multiple turnover ribozymes in nature, the discovery of which earned Sidney Altman and Thomas Cech the Nobel Prize in Chemistry in 1989: in the 1970s, Altman discovered the existence of precursor tRNA with flanking sequences and was the first to characterize RNase P and its activity in processing of the 5' leader sequence of precursor tRNA. Recent findings also reveal that RNase P has a new function. It has been shown that human nuclear RNase P is required for the normal and efficient transcription of various small noncoding RNAs, such as tRNA, 5S rRNA, SRP RNA and U6 snRNA genes, which are transcribed by RNA polymerase III, one of three major nuclear RNA polymerases in human cells.

<span class="mw-page-title-main">Ribonuclease inhibitor</span>

Ribonuclease inhibitor (RI) is a large (~450 residues, ~49 kDa), acidic (pI ~4.7), leucine-rich repeat protein that forms extremely tight complexes with certain ribonucleases. It is a major cellular protein, comprising ~0.1% of all cellular protein by weight, and appears to play an important role in regulating the lifetime of RNA.

Actibind is an actin-binding fungal T(2)-RNase protein that is produced by the black mold Aspergillus niger, a microorganism used in biotechnology and food technology. In plants, actibind binds actin, a major component of the cytoskeleton, interfering with the plants' pollen tubes and halting cell growth. Research published in the journal Cancer on 15 May 2006 reports evidence that actibind has antiangiogenic and anticarcinogenic characteristics. In human colon cancer, breast cancer and melanoma, increasing the level of actibind was found to reduce the ability of these cells to form tumorogenic colonies. In animal models, increased actibind inhibited the growth of colon cancer-derived tumors, metastases and blood vessel formation. During the completion of the Human Genome Project, the gene encoding for RNaseT2, the human actibind-like protein, was found on chromosome 6.

<span class="mw-page-title-main">Pancreatic ribonuclease family</span> Class of enzymes

Pancreatic ribonuclease family is a superfamily of pyrimidine-specific endonucleases found in high quantity in the pancreas of certain mammals and of some reptiles.

<span class="mw-page-title-main">Eosinophil-derived neurotoxin</span> Protein-coding gene in the species Homo sapiens

Eosinophil-derived neurotoxin is an enzyme that in humans is encoded by the RNASE2 gene.

<span class="mw-page-title-main">METAP2</span> Protein-coding gene in humans

Methionine aminopeptidase 2 is an enzyme that in humans is encoded by the METAP2 gene.

<span class="mw-page-title-main">GPR124</span> Protein-coding gene in the species Homo sapiens

Probable G-protein coupled receptor 124 is a protein that in humans is encoded by the GPR124 gene. It is a member of the adhesion-GPCR family of receptors. Family members are characterized by an extended extracellular region with a variable number of protein domains coupled to a TM7 domain via a domain known as the GPCR-Autoproteolysis INducing (GAIN) domain.

<span class="mw-page-title-main">RNASE1</span> Protein-coding gene in the species Homo sapiens

Ribonuclease pancreatic is an enzyme that in humans is encoded by the RNASE1 gene.

<span class="mw-page-title-main">ANTXR1</span> Protein-coding gene in the species Homo sapiens

Anthrax toxin receptor 1 is a protein that in humans is encoded by the ANTXR1 gene. Its molecular weight is predicted as about 63kDa.

<span class="mw-page-title-main">RNH1</span> Protein-coding gene in the species Homo sapiens

Ribonuclease inhibitor is an enzyme that in humans is encoded by the RNH1 gene.

<span class="mw-page-title-main">POP7</span> Protein-coding gene in the species Homo sapiens

Ribonuclease P protein subunit p20 is an enzyme that in humans is encoded by the POP7 gene.

<span class="mw-page-title-main">POP1 (gene)</span> Protein-coding gene in the species Homo sapiens

Ribonucleases P/MRP protein subunit POP1 is a protein that in humans is encoded by the POP1 gene.

<span class="mw-page-title-main">POP5</span> Protein-coding gene in the species Homo sapiens

Ribonuclease P/MRP protein subunit POP5 is an enzyme that in humans is encoded by the POP5 gene.

<span class="mw-page-title-main">Ribonuclease 4</span> Protein-coding gene in the species Homo sapiens

Ribonuclease 4 is an enzyme that in humans is encoded by the RNASE4 gene.

<span class="mw-page-title-main">KIF14</span> Protein-coding gene in the species Homo sapiens

Kinesin-like protein KIF14 is a protein that in humans is encoded by the KIF14 gene.

<span class="mw-page-title-main">AGGF1</span> Protein-coding gene in the species Homo sapiens

Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene.

<span class="mw-page-title-main">RNASEH2A</span> Protein-coding gene in the species Homo sapiens

Ribonuclease H2 subunit A, also known as RNase H2 subunit A, is an enzyme that in humans is encoded by the RNASEH2A gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000214274 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000072115 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 6 7 8 9 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. S2CID   32714925.
  6. 1 2 3 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 . PMID   16961595.
  7. 1 2 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. PMID   12515546.
  8. ↑ 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.
  9. 1 2 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. PMC   3048053 . PMID   21091473.
  10. ↑ 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.
  11. 1 2 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. PMID   11802736.
  12. 1 2 Russo N, Shapiro R, Acharya KR, Riordan JF, Vallee BL (1994). "Role of glutamine-117 in the ribonucleolytic activity of human angiogenin". Proceedings of the National Academy of Sciences. 91 (9): 2920–2924. Bibcode:1994PNAS...91.2920R. doi: 10.1073/pnas.91.8.2920 . PMC   43486 . PMID   8159680.
  13. ↑ 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.
  14. 1 2 Li S, Hu G (2012). "Emerging role of angiogenin in stress response and cell survival under adverse conditions". Journal of Cellular Physiology. 227 (7): 2822–6. doi:10.1002/jcp.23051. PMC   3271170 . PMID   22021078.
  15. ↑ 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 (4): 1352–1360. doi: 10.1158/0008-5472.CAN-04-2058 . PMID   15735021.
  16. ↑ "Entrez Gene: ANG angiogenin, ribonuclease, RNase A family, 5".

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