Biomedical Research-tokyo最新文献

Gq protein-coupled receptors lead to activation of phospholipase C, which triggers phosphoinositide signaling. Diacylglycerol (DG) is one of the phosphoinositide metabolites and serves as a second messenger. Diacylglycerol kinase (DGK) phosphorylates DG to produce another second messenger phosphatidic acid. Of the DGK family, DGKγ is predominantly expressed in the brain at the mRNA level. Recent studies have shown the expression of DGKγ in vascular endothelial cells and adrenal medullary cells at the protein level, although its detailed cellular expression pattern and subcellular localization in the brain remain to be determined. In the present study, we addressed this point using specific DGKγ antibody. DGKγ was expressed in both projection neurons and interneurons in the cerebral cortex, hippocampal formation, and cerebellum. In cerebellar Purkinje cells, DGKγ was distributed to the soma and dendrites. Fractionation study revealed that DGKγ was enriched in the internal membranes containing the endoplasmic reticulum and Golgi complex. In immunoelectron microscopy, DGKγ was localized throughout the smooth endoplasmic reticulum system. These findings suggest that DGKγ shows unique cellular expression pattern in the brain and distinct subcellular localization different from other DGK isozymes.

Dipeptidyl peptidase 4 (DPP4), a serine protease expressed on luminal and apical cell membrane, is identical to the lymphocyte cell surface protein CD26. DPP4 rapidly deactivates hormones and cytokines by cleaving their NH₂-terminal dipeptides. Its functions are based on membrane digestion and/or binding of bioactive peptides, signal molecules, and extracellular matrix components. The soluble form is also present in body fluids such as serum, urine, semen, and synovial fluid. The extremely broad distribution of CD26/DPP4 indicates its divergent roles depending on cell type and activated conditions. The cellular localization was earlier examined by enzyme histochemistry and subsequently by immunohistochemistry. Although immunohistochemical analyses are higher in specificity and easier to use at electron microscopic levels than enzyme histochemistry, the immunoreaction is considerably affected by the animal species, types of tissue sections, and specificity of antibodies. Understanding of the functional significance and advancement of its clinical use (diagnosis and treatment of diseases) require precise information on the cellular distribution including subcellular localization and pathological changes. This short review summarizes in particular immunohistochemical findings on CD26/DPP4.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome. This hereditary cancer is caused by germline variants in MEN1. Two patients with MEN1 were identified via whole exome sequencing and gene expression profile analysis, conducted for 5,063 patients with various types of cancers. We obtained multiple tumors from each patient; tumors derived from these two MEN1 patients had a loss of the normal MEN1 allele and frequently chromosomal copy number changes. Thus, we investigated whether structural variants were present in the MEN1 patient genomes. Whole-genome sequencing revealed no catastrophic rearrangements, and the tumor samples had very low somatic variants. The two patients had germline variants in MEN1 and some chromosomal copy number changes including on chromosome 11. The only pathogenic variant detected was the MEN1 germline variant, and chromosomal rearrangements led to tumorigenesis in somatic cells. Furthermore, the MEN1 tumor samples displayed a specific signature characterized by T:A>C:G transition. Studies of multiple tumors obtained from single patients are rare in hereditary cancer syndromes, and our results provide insights that the second hit of the tumor suppressor gene MEN1 may be caused by a gross genome rearrangement, not a small insertion and deletion, nor a change in epigenetic regulation.