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Abstract
Obestatin, the ghrelin-associated peptide, activates cell proliferation in the gastric cancer cell line KATO-III. The results showed that this peptide induced cell proliferation by mitogen-activated kinase kinase/extracellular signal-regulated kinases1/2 (ERK1/2) phosphorylation. A sequential analysis of the obestatin transmembrane signalling pathway indicated that the ERK1/2 activity is partially blocked after preincubation of the cells with pertussis toxin, as well as by wortmannin (an inhibitor of phosphoinositide 3-kinase (PI3K)), staurosporine (an inhibitor of protein kinase C (PKC)) and 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2, which inhibits the non receptor tyrosine kinase Src). Upon administration of obestatin, the intracellular levels of phospho-PKCε- and θ-isoenzymes rise with similar time-courses, from which PKCε appears to be the responsible for ERK1/2 response. Based on the experimental data, a signalling pathway involving the consecutive activation of Gi, PI3K, novel PKCε and Src for ERK1/2 activation is proposed. These results point to a functionally active peptide that regulates proliferation of the gastric cancer cells KATO-III.
| Abbreviations | ||
| AC | = | adenylyl cyclase |
| ACTH | = | adrenocorticotrophic hormone |
| ANOVA | = | analysis or variance |
| cAMP | = | cyclic adenosine monophosphate |
| DAG | = | diacylglycerol |
| EDTA | = | ethylenediaminetetraacetic acid |
| ERK | = | extracellular signal-regulated kinases |
| FBS | = | fetal bovine serum |
| GH | = | growth hormone |
| GHS-R1a | = | growth hormone secretagogues receptor type 1a |
| GPR39 | = | G protein coupled receptor 39 |
| icv | = | intracerebroventricular |
| LPA | = | lysophosphatidic acid |
| MAPK | = | mitogen-activated protein kinases |
| MEK | = | mitogen-activated kinase kinase |
| PD098059 | = | 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one |
| PI3K | = | phosphoinositide 3-kinase |
| PKA | = | cAMP-dependent protein kinase |
| PKC | = | protein kinase C |
| PMA | = | phorbol myristate acetate |
| PP2 | = | 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine |
| PP3 | = | 4-Amino-7-phenylpyrazol[3,4-d]pyrimidine |
| PS | = | phosphatidylserine |
| PTX | = | pertussis toxin |
| RIPA | = | radioimmuno precipitation assay |
| hRPE | = | human retinal pigment epithelium cells |
| SDS | = | sodium dodecyl sulphate |
| SEM | = | standard error of the mean |
| TBST | = | Tris buffered solution/Tween-20. |
| Abbreviations | ||
| AC | = | adenylyl cyclase |
| ACTH | = | adrenocorticotrophic hormone |
| ANOVA | = | analysis or variance |
| cAMP | = | cyclic adenosine monophosphate |
| DAG | = | diacylglycerol |
| EDTA | = | ethylenediaminetetraacetic acid |
| ERK | = | extracellular signal-regulated kinases |
| FBS | = | fetal bovine serum |
| GH | = | growth hormone |
| GHS-R1a | = | growth hormone secretagogues receptor type 1a |
| GPR39 | = | G protein coupled receptor 39 |
| icv | = | intracerebroventricular |
| LPA | = | lysophosphatidic acid |
| MAPK | = | mitogen-activated protein kinases |
| MEK | = | mitogen-activated kinase kinase |
| PD098059 | = | 2-(2-Amino-3-methoxyphenyl)-4H-1-benzopyran-4-one |
| PI3K | = | phosphoinositide 3-kinase |
| PKA | = | cAMP-dependent protein kinase |
| PKC | = | protein kinase C |
| PMA | = | phorbol myristate acetate |
| PP2 | = | 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine |
| PP3 | = | 4-Amino-7-phenylpyrazol[3,4-d]pyrimidine |
| PS | = | phosphatidylserine |
| PTX | = | pertussis toxin |
| RIPA | = | radioimmuno precipitation assay |
| hRPE | = | human retinal pigment epithelium cells |
| SDS | = | sodium dodecyl sulphate |
| SEM | = | standard error of the mean |
| TBST | = | Tris buffered solution/Tween-20. |
Notes
Grants: FIS and the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (PI050382, P1060239, PI060705 and PI070908) and Xunta de Galicia (PGIDIT05BTF20802PRPGIDIT06PXIB918322PR and PGIDIT06PXIB918360PR).Reprint requests to corresponding author. Disclosure statement: The authors of this manuscript have nothing to declare.