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秦正红:DRAM1 regulates autophagy flux and Bid-mediated cell death via lysosomes
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秦正红,博士,教授,神经药理专业博士生导师。1994年在美国宾州医学院研究生院获博士学位,先后在美国国家卫生研究院(NIH)及麻省总医院和哈佛大学医学院从事研究工作。2003年从哈佛大学引进,现为苏州大学医学部基础医学与生物科学学院科研中心实验室主任,中国药理学会生化药理学专业委员会委员,中国药理学会神经药理学专业委员会委员,美国神经科学学会会员。

Damage-regulated autophagy modulator1 (DRAM1), a novel TP53 target gene, is an evolutionarily conserved lysosomal protein and plays an essential role in TP53-dependent autophagy activation and apoptosis (Crighton et al, 2006). However, the mechanisms by which DRAM1 promotes autophagy and apoptosis are not clear. 3-Nitropropionic acid (3-NP) is an inhibitor of mitochondrial respiratory complex II. Intrastriatal administration of 3-NP produces neuropathology resemble to Huntington disease. 3-NP-induced neuronal death was involved in autophagy and apoptosis. In vitro studies with 3-NP in TP53 wt and null cells, 3-NP or CCCP increased the protein levels of DRAM1 in a TP53-dependent or independent manner. DRAM1 induction contributed to 3-NP-induced autophagy activation. Knock-down of DRAM1 with siRNA inhibited the activity of V-ATPase, acidification of lysosomes and activation of lysosomal proteases. Knock-down of DRAM1 reduced the clearance of autophagososmes.

3-NP also induced a transcription independent upregulation of BAX protein levels. Knock-down of DRAM1 suppressed the increase in BAX levels. Co-immunoprecipitation and pull-down studies revealed an interaction of DRAM1 and BAX protein. Stably expression of exogenous DRAM1 increased the half-life of BAX. Upregulation of DRAM1 recruited BAX to lysosomes and induced cathepsin B-dependent cleavage of Bid and cytochrome c release. Knockdown of DRAM1, BAX or inhibition of lysosomal enzymes reduced 3-NP-induced cytochrome c release and cell death.

These data suggest that DRAM1 plays important roles in regulating autophagy flux and apoptosis. DRAM1 promotes autophagy flux through a mechanism involves activation of V-ATPase and enhances the acidification of lysosomes. DRAM1 promotes apoptosis via a mechanism involving recruitment of BAX to lysosomes to trigger cathepsin B-mediated Bid cleavage.
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讲师介绍
  • 讲师:秦正红(教授)

    博士,教授,神经药理专业博士生导师。1994年在美国宾州医学院研究生院获博士学位,先后在美国国家卫生研究院(NIH)及麻省总医院和哈佛大学医学院从事研究工作。2003年从哈佛大学引进,现为苏州大学医学部基础医学与生物科学学院科研中心实验室主任,中国药理学会生化药理学专业委员会委员,中国药理学会神经药理学专业委员会委员,美国神经科学学会会员。
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