Emerging role of angiogenin in stress response and cell survival under adverse conditions

Abstract

Angiogenin (ANG), also known as ribonuclease (RNASE) 5, is a member of the vertebrate-specific, secreted RNASE superfamily. ANG was originally identified as a tumor angiogenic factor, but its biological activity has been extended from inducing angiogenesis to stimulating cell proliferation and more recently, to promoting cell survival. Under growth conditions, ANG is translocated to nucleus where it accumulates in nucleolus and stimulates ribosomal RNA (rRNA) transcription, thus facilitating cell growth and proliferation. Under stress conditions, ANG is accumulated in cytoplasmic compartments and modulates the production of tiRNA, a novel class of small RNA that is derived from tRNA and is induced by stress. tiRNA suppress global protein translation by inhibiting both cap-dependent and -independent translation including that mediated by weak IRESes. However, strong IRES-mediated translation, a mechanism often used by genes involved in pro-survival and anti-apoptosis, is not affected. Thus, ANG-mediated tiRNA reprogram protein translation, save anabolic energy, and promote cell survival. This recently uncovered function of ANG presents a novel mechanism of action in regulating cell growth and survival.

The Many Virtues of tRNA-derived Stress-induced RNAs (tiRNAs): Discovering Novel Mechanisms of Stress Response and Effect on Human Health

“…However, it is not a general stress response; tRNA cleavage was not observed in ␥-irradiated (4), etoposide-treated, or caffeine-treated human cells (5). Several groups have studied the mechanism of ANG-induced tRNA cleavage (12). The general consensus is that during some stress conditions, ANG-induced tRNA cleavage is either (a) activated by the translocation of ANG into the cytoplasm from the nucleus, thus bringing it into the proximity of its substrates or (b) activated by disassociation of ANG from its cytoplasmic inhibitor ribonuclease/angiogenin inhibitor 1 (RNH1), thus activating its RNase activity (6).…”

“…However, it is not known whether increases in tRNA levels in transformed cells lead to increases in tRNA fragments. Because ANG level is upregulated in several kinds of cancer, it is possible that ANGinduced tRNA halves might be enriched in these scenarios (12,52). Two recent studies have revealed that endogenous tRNA fragments can play important roles in breast cancer and prostate cancer etiology.…”

A Novel Methodology for Structural, Functional and Toxicological Analysis of Mutant Angiogenin Protein in Human

“…ANG also facilitates the production of tiRNA (tRNA-derived stress induced RNA) [8,9] which suppress overall protein translation. tiRNA is important in stress mechanisms under adverse environments utilized by cell [10]. ANG and RNASE4 transcription is regulated by RNA polymerase III and a CCCTC binding factor (CTCF)-depending intragenic chromatin loop [11].…”

Angiogenin is upregulated during the alloreactive immune response and has no effect on the T-cell expansion phase, whereas it affects the contraction phase by inhibiting CD4+ T-cell apoptosis

“…In turn, tiRNAs repress global translation by interfering with translation initiation factors, but specifically facilitate the translation of mRNA that contains internal ribosomal entry sites (IRES) (3)(4)(5). Since numerous IRES-containing mRNAs encode pro-survival and anti-apoptotic genes, angiogenin protects cells from apoptosis during cell stress (6,7). In addition, the direct interaction of angiogenin with p53 (8), and interaction between tiRNAs and cytochrome c released from the mitochondria (9), have been detected to inhibit cell apoptosis.…”

“…The number of PBMCs, from each of the two individuals that contribute to the formation of an MLR couple, was 5x10 5 cells, measuring 1x10 6 PBMCs per well. Resting PMBC cultures of 1x10 6 cells per well from each member of the MLR couple were used as controls.…”