Angiogenin ( ANG) also known as ribonuclease 5 is a small 123 amino acid protein that in humans is encoded by the ANG gene.
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.
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.
Degradation of the basement membrane and 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/
Akt.
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, which subsequently activates other angiogenic factors that induce
angiogenesis.
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).
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.
The presence of Ang inhibitors that block translocation resulted in a decrease of tumor growth and overall angiogenesis.
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.
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.
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
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.
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'
. Each gene splices to a unique downstream exon that contains its complete coding region.
Further reading
External links
