Pancreatic Reg I Binds MKP-1 and Regulates Cyclin D in Pancreatic-Derived Cells

• Published in: The Journal of surgical research Vol. 150; no. 1; pp. 137 - 143
• Main Authors: Mueller, Cathy M., B.S, Zhang, Hong, Ph.D, Zenilman, Michael E., M.D
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2008; Elsevier
• Subjects: Animals; Biological and medical sciences; Cell Line, Tumor; cyclin D1; Cyclin D1 - metabolism; Dual Specificity Phosphatase 1 - metabolism; EXTL3; General aspects; Insulin-Secreting Cells - metabolism; Lithostathine - genetics; Lithostathine - metabolism; MAP Kinase Signaling System; Medical sciences; mitogenesis; Mitosis; MKP-1; Oligonucleotide Array Sequence Analysis; pancreatic ductal cells; Pancreatic Ducts - metabolism; pancreatic reg I; pancreatic β-cells; Rats; Receptors, Cell Surface - metabolism; Surgery; Transfection; Two-Hybrid System Techniques; pancreatic ductal cells; pancreatic β-cells; MKP-1; cyclin D1; mitogenesis; pancreatic reg I; EXTL3; Human; Langerhans islet; Medicine; Regulation(control); Treatment; Surgery; Cell cycle; cyclin Dl; β Cell; Cyclin D; Pancreas
• ISSN: 0022-4804; 1095-8673
• DOI: 10.1016/j.jss.2008.03.047

Background The pancreatic regenerating (reg I) gene and its protein product are derived from acinar cells and are mitogenic to β- and ductal cells. We studied the mechanism of this mitogenic response. Materials and methods ARIP (rat ductal) and RIN 1046–38 (rat β-) cell lines were exposed to exogenous reg I in culture or transfected with a reg I expression vector. Mitogenesis was assessed by MTS assay (CellTiter 96; Promega, Inc., Madison, WI), and cellular mRNA was subjected to gene microarray analysis to determine signal transduction pathways. Yeast two-hybrid technology was then used to determine intracellular binding of reg I protein. Results Cells exposed to exogenous reg I showed a mitogenic response; cells transfected with reg I expression vector showed inhibited growth. Microarray analysis of the former showed induction of cyclin pathways and mitogen-activated protein kinase phosphatase (MKP-1); cyclins were inhibited in the latter. Northern analysis confirmed gene induction of cyclin D1 and MKP-1; JNK was phosphorylated prior to expression of both. Yeast two-hybrid analysis confirmed a protein–protein interaction with MKP-1; this was confirmed by immunoprecipitation. Conclusions Pancreatic-derived cells exposed to reg I grow by activation of signal transduction pathways involving the mitogen-activated protein kinase phosphatases and cyclins, with concomitant induction of MKP-1. However, high intracellular levels of reg I lead to decreased growth, likely via a binding to and inactivation of MKP-1. Inhibition of cell growth, and possible induction of apoptosis, may lead to differentiation of these cells to other cell types.