Proposed pathways for JNK-dependent and JNK-independent apoptosis induction by arsenite and vincristine. (A) Vincristine induced microtubule damage leads to phosphorylation of JNK which, in turn, translocates to the nucleus and phosphorylates the transcription factor c-Jun leading to the induction of multiple nuclear substrates, including c-Jun itself. In addition, activated JNK phosphorylates the cytoplasmic substrate, Bcl-2 at thr-56 leading to its inactivation. The JNK inhibitor SP6 blocks c-Jun induction as well as Bcl-2 phosphorylation leading to an inhibition of apoptosis. Non-lethal heat stress also attenuates vincristine-induced phosphorylation of JNK and Bcl-2 thus blocking the induction of apoptosis. Whether this is due to the stabilization of microtubules by heat stress proteins or by direct effects of hypethermia on the JNK pathway is presently unknown. (B) Global proteotoxic damage induced by arsenite exposure leads to the phosphorylation of JNK that, in turn, phosphorylates the transcription factor c-Jun, leading to the induction of nuclear substrates, including c-Jun itself. However, phosphorylation of the cytoplasmic substrate Bcl-2 does not occur and inhibiting JNK with SP6 does not attenuate apoptosis. Lethal heat stress or arsenite (but not vincristine or non-lethal heat stress) induce a robust p53 response that is associated with apoptosis induction in this scenario.
The contribution of c-Jun N-terminal kinase activation and subsequent Bcl-2 phosphorylation to apoptosis induction in human B-cells is dependent on the mode of action of specific stresses. ()
Donna E. Muscarella, et al. Toxicol Appl Pharmacol. ;228(1):93-104. Figure: F10.
