sst2 Somatostatin Receptor Mediates Cell Cycle Arrest and Induction of p27

Abstract

Activation of the somatostatin receptor sst2 inhibits cell proliferation by a mechanism involving the stimulation of the protein-tyrosine phosphatase SHP-1. The cell cycle regulatory events leading to sst2-mediated growth arrest are not known. Here, we report that treatment of Chinese hamster ovary cells expressing sst2 with the somatostatin analogue, RC-160, led to G 1 cell cycle arrest and inhibition of insulin-induced S-phase entry through induction of the cyclin-dependent kinase inhibitor p27Kip1 . Consequently, a decrease of p27 Kip1 -cdk2 association, an inhibition of insulin-induced cyclin E-cdk2 kinase activity, and an accumulation of hypophosphorylated retinoblastoma gene product (Rb) were observed. However, RC-160 had no effect on the p21 Waf1/Cip1 . When sst2 was coexpressed with a catalytically inactive mutant SHP-1 in Chinese hamster ovary cells, mutant SHP-1 induced entry into cell cycle and down-regulation of p27Kip1 and prevented modulation by insulin and RC-160 of p27Kip1 expression, p27 Kip1 -cdk2 association, cyclin E-cdk2 kinase activity, and the phosphorylation state of Rb. In mouse pancreatic acini, RC-160 reverted down-regulation of p27Kip1 induced by a mitogen, and this effect did not occur in acini from viable motheaten (me v /me v ) mice expressing a mutant SHP-1 with markedly deficient enzymes. These findings provide the first evidence that sst2 induces cell cycle arrest through the up-regulation of p27Kip1 and demonstrate that SHP-1 is required for maintaining high inhibitory levels of p27Kip1 and is a critical target of the insulin, and somatostatin signaling cascade, leading to the modulation of p27Kip1 .

Noninvasive, quantitative imaging in living animals of a mutant dopamine D2 receptor reporter gene in which ligand binding is uncoupled from signal transduction

“…SST2R activation leads to cell cycle arrest and reduced cell proliferation. 26 This property may reduce the potential of the SST2R as a reporter gene, since endogenous ligands may induce undesirable alterations in proliferation or other responses in cells expressing an ectopic SST2R. Uncoupling ligand binding and signal activation may also be useful in optimizing SST2R as an in vivo reporter gene.…”

Expression of neuropeptide hormone receptors in human adrenal tumors and cell lines: Antiproliferative effects of peptide analogues

“…Immunoreactive GHRH receptor was also present in several other neoplasms, including carcinoid tumors, pancreatic cell tumors, small-cell lung cancers, and endometrial neoplasms. Furthermore, adrenal adenomas and PHEO have been shown to secrete GHRH and antagonists of GHRH were found to suppress the growth of human cancer lines, including those from breast, ovary, uterine endometrium, and prostate xenografted into nude mice (13,19,32). In addition, splice variants of GHRH-R have been detected on numerous tumors and found to be distinct from the pituitary GHRH receptors (24).…”

Somatostatin analogues stimulate p27 expression and inhibit the MAP kinase pathway in pituitary tumours

“…Kip1 (6). Cell-cycle progression in mammalian cells requires the co-ordinated action of Cdks and cyclin complexes: p27 is a widely distributed Cdk inhibitor that has a negative influence on cell-cycle progression and it can be used as a prognostic marker in human malignant tumours.…”