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Mechanism of induction of cell differentiation and cell death by inhibitors against V-ATPase

V-ATP酶抑制剂诱导细胞分化和细胞死亡的机制

基本信息

批准号：
09672220
负责人：
OHKUMA Shoji
金额：
$ 2.37万
依托单位：
Kanazawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672220/
关键词：
bafilomycin proton pump PC12 apoptosis neurite outgrowth prodigiosin cell differentiation destruxin パフィロマイシン

项目摘要

In this research project, we have studied the machanism of (1) inhibition of cell growth, (2) induction of cell differentiation, and (3) induction of apoptosis, by V-ATPase inhibitors like bafilomycins, prodigiosins and destruxins, as well as the mechanims of inhibition of proton translocation by these inhibitors.We found (1) that both destrauxin-B and -E inhibited lysosomal proton pump, but only destruxin-E induced induced neurite out growth (NOG) of PC12 cells., (2) that prodigisins uncoupled various proton pump activities due to their H ^+ /Cl symport activity, (3) that prodigiosins, like bafilomycin A ^<1'> induced neurite out growth (NOG), and (4) that the prodigiosin-induced NOG, like bafolomycin-induced one, required de novo synthesis of new messenger RNA as well as protein synthesis, was sensitive to the inhibitors of MAP kinases, serine/threonine phosphatases, tyr-kinases, tyr-phosphatases, calmidulin and phospholipase A ^<2' > but resistant to inhibitors of trk tyrosine kinase and protein kinase A.BE-18591, a tambjamine group antibiotics, also behaved as H ^+ /CU symporters and inhibited hog gastric proton pump, inhibit *cid secretion by gastric parietal cells, inhibited osteoclast differentiation, suppressed proliferation of immune lymphocytes, and induced both NOG and apoptosis, suggesting that the variety of biological activities displayed by these H ^+ /C1 symporters may be due to their H ^+ /C1 symport activity. However, tetrapyrrole, another H ^+ /CV symporter, did not induced NOG.From these results, we conclud that the effect of V-ATPase inhibitors on the intracellular pH does not participate in the variety of biological activities (including induction of NOG) displayed by these compounds.

在本课题中，我们研究了V-ATPase抑制剂如巴菲霉素、prodigiosins和destruxins对细胞生长的抑制、对细胞分化的诱导、对细胞凋亡的诱导机制，以及这些抑制剂对质子易位的抑制机制。我们发现(1)消曲素- b和-E均能抑制溶酶体质子泵，但只有消曲素-E能诱导PC12细胞的诱导神经突外生长（NOG）。(2)由于其H ^+ /Cl同调活性，prodigisins使各种质子泵活性解耦；(3)prodigisins与巴霉素A ^<1'>一样诱导神经突起生长（neurite out growth， NOG）； (4) prodigisins诱导的NOG与巴霉素诱导的NOG一样，需要重新合成新的信使RNA和蛋白质合成，对MAP激酶、丝氨酸/苏氨酸磷酸酶、酪氨酸激酶、酪氨酸磷酸酶、酪氨酸磷酸酶的抑制剂敏感。但对trk酪氨酸激酶和蛋白激酶A. be -18591抑制剂有耐药性的calmidulin和磷脂酶A ^<2' >也作为H ^+ /CU同调体，抑制猪胃质子泵，抑制胃壁细胞分泌*酸，抑制破骨细胞分化，抑制免疫淋巴细胞增殖，诱导NOG和凋亡。提示这些H ^+ /C1同调体表现出的生物活性的多样性可能是由于它们的H ^+ /C1同调活性。然而，另一种H ^+ /CV同调体四吡咯没有引起NOG。从这些结果，我们得出结论，v - atp酶抑制剂对细胞内pH的影响并不参与这些化合物所显示的各种生物活性（包括诱导NOG）。