sst2 somatostatin receptor mediates cell cycle arrest and induction of p27Kip1 -: Evidence for the role of SHP-1

被引:111
作者
Pagès, P
Benali, N
Saint-Laurent, N
Estève, JP
Schally, AV
Tkaczuk, J
Vaysse, N
Susini, C [1 ]
Buscail, L
机构
[1] CHU Rangueil, Inst Louis Bugnard, INSERM, U151, F-31403 Toulouse, France
[2] Tulane Univ, Dept Med, New Orleans, LA 70112 USA
[3] Vet Affairs Med Ctr, Sch Med, New Orleans, LA 70112 USA
[4] CHU Rangueil, Immunol Lab, F-31403 Toulouse, France
关键词
D O I
10.1074/jbc.274.21.15186
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 p27(Kip1). 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 p27(Kip1) and prevented modulation by insulin and RC-160 of p27(Kip1) 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 p27(Kip1) 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 p27(Kip1) and demonstrate that SHP-1 is required for maintaining high inhibitory levels of p27(Kip1) and is a critical target of the insulin, and somatostatin signaling cascade, leading to the modulation of p27(Kip1).
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页码:15186 / 15193
页数:8
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