Serum mannan binding protein (MBP), a mannose/N-acetylglusosamine-specific lectin, is important in innate immunity. In order to elucidate the mechanism underlying the wide intra- and interracial variety in the MBP serum level, we have studied the transcriptional regulation of human MBP. Rapid amplification of cDNA ends (5' RACE) analysis of Hep G2 RNA indicated the presence of a novel exon, designated as "exon 0," upstream of previously identified exon 1 [Taylor, M.E. et al. (1989) Biochem. J. 262, 763-771]. Two MBP mRNAs with different sized 5'-noncoding regions were detected: the longer transcript starts at exon 0 and the shorter one at exon 1. Promoter analysis involving a luciferase assay vector revealed that the transcript starting from exon 1 predominates over that starting from exon 0. In addition, a hepatocyto-specific nuclear factor, (HNF)-3, which is known to control the expression of hepatocyto-specific genes, up-regulates the transcription of human MBP from exon 1, while a glucocorticoid, which is known to up-regulate acute phase proteins, markedly suppresses MBP transcription. Recently, polymorphisms were found to occur in the promoter region at two positions [Madsen, H.O. et al. (1995) J. Immunol. 155, 3013-3020]. Functional promoter analysis indicated that three haplotype variants as to these positions, HY, LY, and LX, exhibit high, medium and low promoter activity, respectively, in accordance with the results of a previous population study.
Leucine zipper-bearing kinase (LZK) is a novel member of the mixed lineage kinase (MLK) protein family, the cDNA of which was first cloned from a human brain cDNA library [Sakuma, H., Ikeda, A., Oka, S., Kozutsumi, Y., Zanetta, J.-P., and Kawasaki, T. (1997) J. Biol. Chem. 272, 28622-28629]. Several MLK family proteins have been proposed to function as MAP kinase kinase kinases in the c-Jun NH(2) terminal kinase (JNK)/stress-activated protein kinase (SAPK) pathway. In the present study, we demonstrated that, like other MLKs, LZK activated the JNK/SAPK pathway but not the ERK pathway. LZK directly phosphorylated and activated MKK7, one of the two MAPKKs in the JNK/SAPK pathway, to a comparable extent to a constitutive active form of MEKK1 (MEKK1DeltaN), suggesting a biological role of LZK as a MAPKKK in the JNK/SAPK pathway. Recent studies have revealed the essential roles of scaffold proteins in intracellular signaling pathways including MAP kinase pathways. JIP-1, one of the scaffold proteins, has been shown to be associated with MLKs, MKK7, and JNK [Whitmarsh, A.J., Cavanagh, J., Tournier, C., Yasuda, J., and Davis, R.J. (1998) Science 281, 1671-1674], suggesting the presence of a selective signaling pathway including LZK, MKK7, and JNK. Consistent with this hypothesis, we provided evidence that LZK is associated with the C-terminal region of JIP-1 through its kinase catalytic domain. In addition, LZK-induced JNK activation was markedly enhanced when LZK and JNK were co-expressed with JIP-1. These results constituted important clues for understanding the molecular mechanisms regulating the signaling specificities of various JNK activators under different cellular conditions.
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