Analysis of transcrition regulators involved in intracellular signaling

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A number of transcription factors of ATF/CREB family have been identified so far. This group of proteins contains the DNA-binding domain consisting of the cluster of basic amino acids and the leucine zipper, so-called b-zip. Among many transcription factors of ATF/CREB family, three factors, CRE-BP1 (also called ATF-2), ATF-a, and CRE-BPa forms a subgroup. This group of factors forms a homodimer or heterodimer with c-Jun, and binds to CRE.The stress-activated kinases (SAPK) such as Jun amino-terminal kinase (JNK) and p38 phosphorylates this group of factors at the sites close to the N-terminal transcriptional activation domain, and stimulate their trans-activating capacity. Since a group of factors of the ATF/CREB family including CREB are activated via direct phosphorylation by cAMP-dependent protein kinase (PKA), these two groups of factors are linked to the distinct signaling cascades, PKA and SAPK pathways.To investigate the physiological role od CRE-BP1 genefamly, we made the knockout mice of CRE-BP1, CRE-BPa, and ATF-a genes. The mouse null mutant of CRE-BP1 died shortly after birth with symptoms of severe respiratory distress, and that the mutant lung was filled with meconium like human meconium aspiration syndrome (MAS) which is a common neonatal problem. The decreased trophobalst proliferation in the mutant placenta and the occurrence of hypoxia in the mutant embryos were observed at 18.5 dpc. Anomalies in placenta may cause the insufficient oxgen supply followed by gasping respirations and aspiration of the amniotic fluid containing meconium. The expression level of PDGF receptor alpha gene which plays an important role for proliferation of trophoblast, was found to be decreased in the trophoblasts of mutant placenta. The CRE-BP1 null mutants will be useful to understand the mechanisms of MAS and to develop the therapy for MAS.