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Volume 272, Number 26, Issue of June 27, 1997 pp. 16364-16373
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Expression of Mixed Lineage Kinase-1 in Pancreatic -Cell Lines at Different Stages of Maturation and during Embryonic Pancreas Development

(Received for publication, July 25, 1996, and in revised form, March 7, 1997)

Henry J. DeAizpurua , David S. Cram , Gaetano Naselli , Lisa Devereux ^¶ and Donna S. Dorow ^¶

From the  Burnet Clinical Research Unit, Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Parkville 3050, Australia and ^¶ Trescowthick Research Laboratories, Peter MacCallum Cancer Institute, Locked Bag 1 A'Beckett Street, Melbourne 3000, Australia

Events controlling differentiation to insulin-secreting -cells in the pancreas are not well understood, although -cells are thought to arise from pluripotent ductal precursor cells. To search for signaling proteins that might be involved in -cell maturation, we analyzed protein kinase expression in two developmentally and functionally distinct pancreatic -cell lines, RIN-5AH and RIN-A12, by reverse transcriptase polymerase chain reaction. A number of tyrosine and serine/threonine kinases were identified in both lines. One protein kinase, mixed lineage kinase-1 (MLK-1), was expressed at both the RNA and protein levels in RIN-5AH cells, which display an immature -cell phenotype, but was not detected in the more mature RIN-A12 cells. Furthermore, levels of MLK-1 mRNA and protein were increased after brief stimulation of RIN-5AH cells with either the differentiation inducer, sodium butyrate, or with serum after serum starvation. These increases in expression were independent of phenotypic markers such as insulin secretion or surface expression of major histocompatibility class I- and A2B5-reactive ganglioside. In addition, increases in MLK-1 expression in the stimulated RIN-5AH cells were accompanied by phosphorylation of MLK-1 on serine but not tyrosine. Antisense oligonucleotides to two distinct regions of MLK-1 caused RIN-5AH cells, but not RIN-A12 cells, to adopt a highly undifferentiated morphology, with a reduction in DNA synthesis and MLK-1 protein levels and elevated glucagon mRNA levels, but with no effect on insulin mRNA. In an immunohistochemical survey of embryonic mouse tissues, we found that temporal expression of MLK-1 was regulated in a tissue-specific manner. In the embryonic pancreas, MLK-1 expression was evident in ductal cells from day 13 to 16 but was not detected in late stage gestation or neonatal pancreas. These data suggest that MLK-1 is regulated in immature pancreatic -cells and their ductal precursors at the level of functional maturity and may therefore play a role in -cell development.

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