Signal transduction mechanisms through granulocyte colony-stimulating factor receptor.

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In order to clarify the signal transduction mechanisms of growth suppression during G-CSF induced neutrophil differentiation, gene expressions of cell-cycle regulatory proteins and transcription factors which are involved in granulocyte differentiation were examined in neutrophil progenitor cells GM-162M and 32Dcl3 by Northern blot hybridization. Gene expression of cyclin dependent kinase inhibitor p21^<WAF1> was not increased by G-CSF stimulation, while levels of mRNA for p27^<KIP1> and p19^<INK4D> were elevated. On the other hand, expression of transcription factors C/EBPα and C/EBPε genes, which were possibly involved in the granulocyte differentiation, was induced by G-CSF stimulation, while quantity of PU.1 mRNA was unaffected. Therefore, expression of p27^<KIP1> and p19^<INK4D> appeared to prevent the cell-cycle progression from G1 to S during G-CSF dependent neutrophil differentiation. It's also possible that C/EBPα and/or C/EBPε transcription factors control the gene expression … More of these CDK inhibitors.We have been trying to identify genes which express in cells capable of responding to G-CSF for neutrophil differentiation but not in the cells with mutant G-CSF receptor unable to respond for the differentiation, thereby being involved in neutrophil differentiation. Using PCR-based subtraction-hybridization technique, several genes were identified including genes for Stat3 and ERO1-L.G-CSF stimulation induces phosphorylation and dimerization of Stat3 which is then transferred to nucleus where Stat3 activates transcription of its target genes. Stat3 activation is known to be necessary for G-CSF dependent neutrophil differentiation. Our data showed that activated Stat3 turns on the expression of its own genes, which produces more Stat3 protein. This mechanism seems to accelerate G-CSF dependent neutrophil differentiation. Moreover, ERO1-L is a enzyme involved in the protein disulfide-bond formation in ER and in formation of tertiary structure of nascent polypeptide. G-CSF dependent expression of ERO1-L gene appeared to be in control of Stat3 activation during neutrophil differentiation. Therefore, ERO1-L seems to help synthesizing bacteriocidal proteins such as MPO and elastase into ER during neutrophil differentiation. Less