ASK1-dependent recruitment and activation of macrophages induce hair growth in skin wounds.

Apoptosis signal-regulating kinase 1 (ASK1) is a member of the mitogen-activated protein 3-kinase family that activates both c-Jun NH(2)-terminal kinase and p38 pathways in response to inflammatory cytokines and physicochemical stress. We report that ASK1 deficiency in mice results in dramatic retardation of wounding-induced hair regrowth in skin. Oligonucleotide microarray analysis revealed that expression of several chemotactic and activating factors for macrophages, as well as several macrophage-specific marker genes, was reduced in the skin wound area of ASK1-deficient mice. Intracutaneous transplantation of cytokine-activated bone marrow-derived macrophages strongly induced hair growth in both wild-type and ASK1-deficient mice. These findings indicate that ASK1 is required for wounding-induced infiltration and activation of macrophages, which play central roles in inflammation-dependent hair regrowth in skin.

Mitochondrial phosphoglycerate mutase 5 uses alternate catalytic activity as a protein serine/threonine phosphatase to activate ASK1.

Phosphoglycerate mutase (PGAM) is an enzyme of intermediary metabolism that converts 3-phosphoglycerate to 2-phosphoglycerate in glycolysis. Here, we discovered PGAM5 that is anchored in the mitochondrial membrane lacks PGAM activity and instead associates with the MAP kinase kinase kinase ASK1 and acts as a specific protein Ser/Thr phosphatase that activates ASK1 by dephosphorylation of inhibitory sites. Mutation of an active site His-105 in PGAM5 abolished phosphatase activity with ASK1 and phospho-Thr peptides as substrates. The Drosophila and Caenorhabditis elegans orthologs of PGAM5 also exhibit specific Ser/Thr phosphatase activity and activate the corresponding Drosophila and C. elegans ASK1 kinases. PGAM5 is unrelated to the other known Ser/Thr phosphatases of the PPP, MPP, and FCP families, and our results suggest that this member of the PGAM family has crossed over from small molecules to protein substrates and been adapted to serve as a specialized activator of ASK1.

Molecular characterization and expression of the teleost cytosolic DNA sensor genes cGAS, LSm14A, DHX9, and DHX36 in Japanese medaka, Oryzias latipes.

Numerous cytosolic DNA sensors (CDSs), which are very important for recognizing cytosolic dsDNA derived from intracellular viruses and bacteria, exist in mammals. However, teleost CDSs are poorly understood. In this study, four CDSs, including the cyclic GMP-AMP synthase (cGAS), Sm-like protein 14 homolog A (LSm14A), DEAH-box helicase (DHX) 9, and DHX36 genes were identified in Japanese medaka, Oryzias latipes, and their expression patterns were elucidated. The expression of these genes was upregulated in the intestines and kidney of CpG-ODN-stimulated medaka. The cGAS and LSm14A genes were significantly induced in the intestines, kidney, and spleen of formalin-killed Edwardsiella tarda-treated medaka; the DHX9 and DHX36 genes were not. cGAS gene expression was induced only in the intestines of live E. tarda-treated medaka. These results suggest that the transcription of four CDS genes of medaka responds to dsDNA stimulation, and cGAS is probably more important for the immune response against E. tarda infection.

Stress signaling in cancer.

The human body is continuously exposed to a wide variety of physical, chemical, and biological stress stimuli from both the external and internal environments. In order to adapt to or resist stress, cells are equipped with multiple signaling systems, which elicit a wide range of stress responses. Stress signaling also operates to eliminate cells with severe stress-induced damage through the induction of apoptosis. Once stress signaling is compromised in certain adverse conditions, however, cells exhibit aberrant responses to stress, which can eventually cause various diseases including cancer. In the present review, the authors focus on the current understanding of the critical linkage between stress signaling and cancer.