p38 MAP Kinase Mediates Nitric Oxide-induced Apoptosis of Neural Progenitor Cells

Abstract

Neural progenitor cells (NPC) can proliferate, differentiate into neurons or glial cells, or undergo a form of programmed cell death called apoptosis. Although death of NPC occurs during development of the nervous system and in the adult, the underlying mechanisms are unknown. Here we show that nitric oxide (NO) can induce death of C17.2 NPC by a mechanism requiring activation of p38 MAP kinase, poly(ADP-ribose) polymerase, and caspase-3. Nitric oxide causes release of cytochrome c from mitochondria, and Bcl-2 protects the neural progenitor cells against nitric oxide-induced death, consistent with a pivotal role for mitochondrial changes in controlling the cell death process. Inhibition of p38 MAP kinase by SB203580 abolished NO-induced cell death, cytochrome c release, and activation of caspase-3, indicating that p38 activation serves as an upstream mediator in the cell death process. The antiapoptotic protein Bcl-2 protected NPC against nitric oxide-induced apoptosis and suppressed activation of p38 MAP kinase. The ability of nitric oxide to trigger death of NPC by a mechanism involving p38 MAP kinase suggests that this diffusible gas may regulate NPC fate in physiological and pathological settings in which NO is produced.

Opposing Roles of c-Jun NH2-Terminal Kinase and p38 Mitogen-Activated Protein Kinase in the Cellular Response to Ionizing Radiation in Human Cervical Cancer Cells

“…Many reports suggested that JNK or p38 MAPK induces apoptosis by regulating the translocation of Bax from the cytoplasm to the mitochondria in response to various stimuli (12)(13)(14). These results are consistent with the fact that JNK and/ or p38 MAPK acts at early step before dysfunction of mitochondria and caspase activation in several cell types (15)(16)(17). In contrast, recent observations showed that p38 MAPK is a critical regulator of cell survival and proliferation in response to cisplatin, camptothecin, doxorubicin, UV irradiation, and repetitive low-grade oxidative stress (18)(19)(20).…”

“…Many reports suggested that p38 MAPK induces apoptotic cell death in response to various stimuli (15)(16)(17). In contrast, in this study we showed that p38 MAPK played a role in cell survival response against radiation-induced mitochondrial cell death.…”

Effect of neural precursor proliferation level on neurogenesis in rat brain during aging and after focal ischemia

“…Caspase family members are key elements of programmed cell death in the developing nervous system [26], where this form of cell death affects both NPCs and postmitotic neurons. Activation of caspase-3 is required for embryonic and perinatal apoptosis of NPCs [21], which is inhibited by Bcl-2 [12]. In addition, in vitro studies show that caspase-3 is activated in NPCs undergoing neurotoxin-induced death in the adult brain [10].…”

Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) pathway

“…Both JNK and p38 have been reported to mediate apoptosis in neural lineage cells. Nitric oxide induced apoptosis through p38 activation in neural progenitor cells (Cheng et al, 2001), whereas nutrient deprivation induced apoptosis through JNK activation in neurons. (Harris and Johnson, 2001).…”