| Co-Investigator(Kenkyū-buntansha) |
SOMEI Masanori Kanazawa University, Pharmaceutical Sciences, Professor, 薬学部, 教授 (20110546)
YOKOYAMA Ken Kanazawa University, Pharmaceutical Sciences, Assistance, 薬学部, 助手 (70271377)
ARAI Kunizo Kanazawa University, Pharmaceutical Sciences, Assistant Professor, 薬学部, 講師 (50126562)
OHTA Tetsuo Kanazawa University, Pharmaceutical Sciences, Associate Professor, 医学部・附属病院, 助教授 (40194170)
HATANAKA Yasumaru Toyama Medical Pharmaceutical University, Pharmaceutical Sciences, Professor (30111181)
|
|---|
| Research Abstract |
In this project, we have investigated the role of autophagy in the induction of neurite outgrowth (NOG), growth inhibition and apoptosis by a new type of H^+/CL^- symporting antibiotics like prodigiosins.
We found the followings: (1) Prodigiosins, like bafilomycins, inhibited pancreatic cancer transplanted into nude mice. (2) Prodigiosins also induced apoptosis and NOG in RNA_-, protein-syntheses, and serine/threonine kinase-dependent manners, and K_-252_<a-> or A_-kinase-independent manners, but induced apoptosis differently from NOG in its in-sensitivity to tyrosine phosphates inhibitors. (3) E-58591, a prodigiosin-like tambjamine antibiotics, also showed H^+/CL^- symport activity and strongly inhibited spleen cell immune responses, gastric acid secretion and inhibited osteoclastosis and induced NOG at higher concentrations. (4) We have succeeded in the synthesis of affinity probe for concanamycins (analogs of bafilomycins) and showed concanamycin-induced NOG from outside of plasma membranes. (5) 3-Methyladenine, and inhibitor against autophagy, did not induce apoptosis in the presence of serum, suggesting little participation of autophapy on the bafilomycin-induced apoptosis. (6) We isolated human-homologs of autophagy-related genes from HeLa cells. They showed cell death of CHO in the absence of amino acid- or serum-free medium. (7) We established a system to look into degradation of GFP-labeled organelles (mitochondria and peroxisomes). (8) We showed that apoptosis and NOG was not induced by pH-differences between inside and outside of cells, because they were not induced by NH_4Cl. (9) Prodigiosins also strongly and reversibly uncoupled (H^+/K^+) ATPase-dependent proton-translocation from rabbit gastric mucosa. (10) We have succeeded in the cloning, proton pump-dependent ATP synthesis, and determation of operon structure of V-ATPase from a eubact rium (Thermus termophilus).
|
