Signal transduction of somatostatin receptors negatively controlling cell proliferation

Somatostatin acts as an inhibitory peptide of various secretory and prolife rative responses. Its effects are mediated by a family of G-protein-coupled receptors (sst1-5) that can couple to diverse signal transduction pathways such as inhibition of adenylate cyclase and guanylate cyclase, modulation of ionic conductance channels, and protein dephosphorylation. The five rece ptors bind the natural peptide with high affinity but only sst2, sst5 and s st3 bind the short synthetic analogues. Somatostatin negatively regulates t he growth of various normal and tumour cells. This effect is mediated indir ectly through inhibition of secretion of growth-promoting factors, angiogen esis and modulation of the immune system. Somatostatin can also act directl y through sst receptors present on target cells. The five receptors are exp ressed in various normal and tumour cells, the expression of each receptor being receptor subtype and cell type specific. According to the receptor su btypes, distinct signal transduction pathways are involved in the antiproli ferative action of somatostatin. Sst1, 4 and 5 modulate the MAP kinase path way and induce GI cell cycle arrest. Sst3 and sst2 promote apoptosis by p53 -dependent and -independent mechanisms, respectively. (C) 2000 Elsevier Sci ence Ltd. Published by Editions scientifiques et medicales Elsevier SAS.