2,2',3,3',4,4'-Hexahydroxy-1,1'-biphenyl-6,6'-dimethanol dimethyl ether (HBDDE)-induced neuronal apoptosis independent of classical protein kinase C alpha or gamma inhibition.
2,2',3,3',4,4'-Hexahydroxy-1,1'-biphenyl-6,6'-dimethanol dimethyl ether (HBDDE)-induced neuronal apoptosis independent of classical protein kinase C alpha or gamma inhibition.
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2,2,3,3,4,4-六羟基-1,1-联苯-6,6-二甲醇二甲醚 (HBDDE) 诱导的神经元凋亡与经典蛋白激酶 C α 或 γ 抑制无关。
DOI：
10.1016/s0006-2952(00)00398-1
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发表时间：
2000
影响因子：
5.8
通讯作者：
Vallano,ML
中科院分区：
文献类型：
--
作者：
Mathur,A;Vallano,ML
Protein kinase C (PKC) isozymes constitute a family of at least 12 structurally related serine–threonine kinases that are differentially regulated and localized, and are presumed to mediate distinct intracellular functions. To explore their roles in intact cells, investigators are developing cell-permeable, isoform-selective inhibitors. 2,2′,3,3′,4,4′-Hexahydroxy-1,1′-biphenyl-6,6′-dimethanol dimethyl ether (HBDDE) is reported to be a selective inhibitor of PKC α and γ with ic50values of 43 and 50 μM, respectively, using an in vitro assay. However, data examining the potency and selectivity of HBDDE in intact cells are lacking. Employing rodent cerebellar granule neurons as a model system, we investigated the effects of HBDDE using cell survival as a functional end-point. HBDDE induced an apoptotic form of cell death that was dependent upon protein synthesis and included activation of a terminal executioner of apoptosis, caspase 3. The concentration of HBDDE required for half-maximal cell death was less than 10 μM (∼5-fold less than the reported ic50values for PKC α and γ in vitro). Furthermore, HBDDE induced apoptosis even after phorbol-ester-mediated down-regulation of PKC α and γ, indicating that this effect is independent of these isoforms. Consistent with this, 2-[1-(3-dimethylaminopropyl) indol-3-yl]-3-(indol-3-yl)-maleimide (GF 109203X), a general inhibitor of all classical and some novel PKCs, did not interfere with survival. Thus, HBDDE should not be used as an isoform-selective inhibitor of PKC α or γ in intact cells. Nevertheless, identification of its target in granule neurons will provide valuable information about survival pathways.
