Angiogenin-mediated rRNA transcription in cancer and neurodegeneration.

Angiogenin (ANG) is a 14 kDa angiogenic ribonuclease that is upregulated in a variety of human cancers. Accumulating evidence indicates that the angiogenic activity of ANG is related to its ability in regulating ribosomal RNA (rRNA) transcription. ANG is translocated to the nucleus of growth-stimulated endothelial cells where it accumulates in the nucleolus, binds to the promoter region of ribosomal DNA (rDNA), and stimulates rRNA transcription. This normally well-controlled process of nuclear translocation of ANG is hijacked by cancer cells that constitutively uptake ANG and translocate it into the nucleus so that rRNA is constantly transcribed to meet a higher metabolic requirement of this cells. Nuclear translocation of ANG therefore controls the rate of rRNA transcription and has been shown to be a molecular target for cancer drug development. Recently, ANG has also been shown to play a role in motor neuron physiology. Loss-of-function mutations in the coding region of ANG gene have been found in patients with amyotrophic lateral sclerosis (ALS). A deficiency in ANG function may result in insufficient rRNA transcription in motor neurons that require robust ribosome biogenesis due to the demand of long axonal transport. Haploinsufficiency of ANG has thus been implicated in ALS pathogenesis, and ANG has been shown to promote motor neuron survival both in vitro and in vivo. Promotion of ANG expression or activity has been recognized as a therapeutic opportunity for ALS treatment.