Signal transduction mechanisms through granulocyte colony-stimulating factor receptor.

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To analyze the mechanisms of neutrophil differentiation, murine homologue (MZF-2) of human MZF-1 cDNA, which encodes the transcription factor. involved in neutrophil differentiation, was isolated. C-terminus region of MZF-2 protein containing zinc finger domain is highly homologous to that of the MZF-1, However, the amino-terminus of MZF-2 protein was different from that of MZF-1 protein in that MZF-2 protein has leucine rich region (LeR domain) and a region rich in acidic amino acids. The chromosomal gene of MZF-2 consist of 5 exons and alternative transcription start sites of the gene produce MZF-1 and MZF-2 mRNAs. The analysis of transcription activation activities of amino-terminus deletion derivatives of MZF-2 revealed that amino-terminus region interacted to the transcription-activation domain and suppressed its own transcriptional activation.On the other hand, G-CSF dependent phospho-proteins, which can bind to the tyrosine-phosphorylated G-CSF receptor, were isolated. The N-terminal amino-acid sequence of one of those was identical to that of SHIP.Its G-CSF dependent tyrosine phosphorylation and interaction with G-CSF receptor were demonstrated.Furthermore, I examined G-CSF dependent expression of several anti-apoptotic genes. One of them, bcl-2, was found to be expressed about 3 hours after G-CSF stimulation. As the gene was not expressed in cells carrying G-CSF receptor with mutated 4th cytoplasmic tyrosine residue, the 4th tyrosine residue of the receptor seemed to be involved in the anti-apoptotic signal transduction.Moreover, alpha-D-mannnosidase and macrophage inflammatory protein 1-alpha genes were found to be expressed 15 minutes after G-CSF stimulation.