Angiogenin

Angiogenin (Ang) also known as ribonuclease 5 is a small 123 amino acid is_associated_with::protein that in humans is encoded by the ANG is_associated_with::gene. Angiogenin is a potent stimulator of new blood vessels through the process of is_associated_with::angiogenesis. Ang hydrolyzes cellular is_associated_with::RNA, resulting in modulated levels of protein synthesis and interacts with is_associated_with::DNA causing a promoter-like increase in the expression of is_associated_with::rRNA. Ang is associated with cancer and neurological disease through is_associated_with::angiogenesis and through activating gene expression that suppresses is_associated_with::apoptosis.

Function
Angiogenin is a key protein implicated in is_associated_with::angiogenesis in normal and tumor growth. Angiogenin interacts with is_associated_with::endothelial and is_associated_with::smooth muscle cells resulting in cell migration, invasion, proliferation and formation of tubular structures. Ang binds to is_associated_with::actin of both smooth muscle and is_associated_with::endothelial cells to form complexes that activate is_associated_with::proteolytic cascades which upregulate the production of is_associated_with::proteases and is_associated_with::plasmin that degrade the is_associated_with::laminin and is_associated_with::fibronectin layers of the is_associated_with::basement membrane. Degradation of the is_associated_with::basement membrane and is_associated_with::extracellular matrix allows the endothelial cells to penetrate and migrate into the perivascular tissue. 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/is_associated_with::Akt. Activation of these proteins leads to invasion of the basement membrane and is_associated_with::cell proliferation associated with further is_associated_with::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 is_associated_with::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 is_associated_with::angiogenesis.

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

Cancer
Ang has a prominent role in the pathology of is_associated_with::cancer due to its functions in is_associated_with::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 is_associated_with::rRNA, while knockdown strains of Ang cause downregulation. The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis. is_associated_with::HeLa cells translocate Ang to the nucleus independent of cell density. In is_associated_with::human umbilical vein endothelial cells(HUVEC), translocation of Ang to the nucleus stops after cells reach a specific density, while in is_associated_with::HeLa cells translocation continued past that point. Inhibition of Ang affects the ability of is_associated_with::HeLa cells to proliferate, which proposes an effective target for possible therapies.

Neurodegenerative diseases
Due to the ability of Ang to protect is_associated_with::motoneurons (MNs), causal links between Ang mutations and is_associated_with::Amyotrophic lateral sclerosis (ALS) are likely. The angiogenic factors associated with Ang may protect the central nervous system and MNs directly. 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. Angiogenin expression in Parkinson's disease is dramatically decreased in the presence of is_associated_with::alpha-synuclein (α-syn) aggregations. Exogenous angiogenin applied to is_associated_with::dopamine-producing cells leads to the is_associated_with::phosphorylation of PKB/is_associated_with::AKT and the activation of this complex inhibits cleavage of is_associated_with::caspase 3 and is_associated_with::apoptosis when cells are exposed to a is_associated_with::Parkinson's-like inducing substance.

Gene
is_associated_with::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' is_associated_with::exons. Each gene splices to a unique downstream exon that contains its complete coding region.