Mitochondrial targeting of JNK/SAPK in the phorbol ester response of myeloid leukemia cells

Abstract

Treatment of human U-937 myeloid leukemia cells with 12-Otetradecanoylphorbol-13-acetate (TPA) is associated with activation of the stress-activated protein kinase (SAPK) and induction of terminal monocytic differentiation. The present studies demonstrate that TPA targets SAPK to mitochondria by a mechanism dependent on activation of protein kinase C (PKC) b. Translocation of SAPK to mitochondria in response to TPA is associated with release of cytochrome c, caspase-3 activation and induction of apoptosis. The results show that TPA induces the association of SAPK with the mitochondrial anti-apoptotic Bcl-x L protein. Overexpression of Bcl-x L attenuated the apoptotic response to TPA treatment. Moreover, expression of Bcl-x L mutated at sites of SAPK phosphorylation (Thr-47, -115) was more effective than wildtype Bcl-x L in abrogating TPA-induced cytochrome c release and apoptosis. By contrast, expression of Bcl-x L had little effect on induction of the monocytic phenotype. These findings indicate that myeloid leukemia cells respond to TPA with targeting of SAPK to mitochondria and that this response contributes to terminal differentiation through the release of cytochrome c and induction of apoptosis. Cell Death and Differentiation (2001) 8, 794 ± 800.

Oxidant-Mediated Mitochondrial Injury in Eosinophil Apoptosis: Enhancement by Glucocorticoids and Inhibition by Granulocyte-Macrophage Colony-Stimulating Factor

“…JNK, a member of the mitogen-activated protein family of serinethreonine kinases activated by stress, (and particularly within minutes following oxidant stress), is thought to contribute to apoptosis in many cell types (38,39,57). Of note, we did not find evidence for JNK activation in eosinophil apoptosis in the absence of GC treatment.…”

“…In other cells, activated JNK has been shown to associate with, and phosphorylate, the antiapoptotic proteins Bcl-2 and Bcl-x L and alter their effects. Phosphorylation of the latter has been shown to lead to mitochondrial injury and apoptosis; while overexpression of Bcl-x L , with mutated sites blocking phosphorylation by JNK, inhibited mitochondrial injury and apoptotic death (38,39). Thus it is suggested that JNK activation may alter the functional balance and activities of these anti-and proapoptotic Bcl-2 family members in eosinophils.…”

“…Oxidants can lead to JNK activation, which has been associated with induction of apoptosis in other cells (38,39), and dexamethasone has been shown previously to activate JNK in eosinophils (13). To determine whether JNK activation was due to the elicited oxidants, eosinophils were treated with and without dexamethasone in the presence or absence of DPI.…”

Oxaliplatin Sensitizes Human Colon Cancer Cells to TRAIL Through JNK-Dependent Phosphorylation of Bcl-xL

“…31 An-other study suggested that activated JNK might translocate to mitochondria and associate with Bcl-xL in response to cellular stress. 32 It also was reported that activation of JNK signaled mitochondrial translocation of Bax and Bcl-2 phosphorylation, resulting in mitochondrial apoptotic cell death. 33 In line with these findings, we show here that oxaliplatin-mediated Bcl-xL phosphorylation was dependent on JNK activation as shown by the use of JNK inhibitors or by JNK siRNA.…”

MyD88-5 links mitochondria, microtubules, and JNK3 in neurons and regulates neuronal survival

“…Diverse stresses, such as oxidative injury and infl ammatory cytokines, induce activation ( 58 ) and translocation of JNKs to mitochondria, where JNKs promote apoptosis ( 37,59 ) by multiple mechanisms. JNK3 binds and inhibits the antiapoptotic proteins Bcl-2 ( 60 ) and Bcl-xL ( 37 ), mediates phosphorylation and oligomerization of the proapoptotic protein BAD ( 61 ), and promotes translocation of the proapoptotic protein BAX from the cytoplasm to mitochondria ( 62 ).…”