Nicotine Inactivation of the Proapoptotic Function of Bax through Phosphorylation

Xin, Meiguo; Deng, Xingming

doi:10.1074/jbc.m500084200

Cited by 210 publications

(210 citation statements)

References 44 publications

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“…Serine 184 is at the end of the hydrophobic C-terminus; its phosphorylation by protein kinase C (PKC) zeta (Xin et al, 2007) or AKT (Xin and Deng, 2005) inactivates Bax, and conversely its de-phosphorylation by protein phosphatase 2A activates Bax by promoting exposure of the N-terminus (Xin and Deng, 2006). Ser 184 plays a key role in controlling Bax sub-cellular localization (Nechushtan et al, 1999).…”

Section: Critical Amino Acid Residuesmentioning

confidence: 99%

Multistep and multitask Bax activation

Ghibelli

Diederich

2010

Mitochondrion

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Bax is a pro-apoptotic protein allowing apoptosis to occur through the intrinsic, damage-induced pathway, and amplifying that one occurring via the extrinsic, receptor mediated pathway. Bax is present in viable cells and activated by pro-apoptotic stimuli. Activation implies structural changes, consisting of exposure of the N terminus and hydrophobic domains; changes in localization, consisting in migration from cytosol to mitochondria and endoplasmic reticulum membranes; changes in the aggregation status, from monomer to dimer and multimer. Bax has multiple critical domains, namely the N terminus exposed after activation; two hydrophobic stretches exposed for membrane anchorage; two reactive cysteines allowing multimerization; the BH3 domain for interactions with the Bcl-2 family members; alpha helix 1 for t-Bid interaction. Bax has also multiple functions: it releases different mitochondrial factors such as cytochrome c, SMAC/diablo; it regulates mitochondrial fission, the mitochondrial permeability transition pore; it promotes Ca 2+ leakage through ER membrane. Altogether, Bax activation is a complex multi-step phenomenon. Here, we analyze these events as logically separable or alternative steps, attempting to assess their role, timing and reciprocal relation.

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Section: Critical Amino Acid Residuesmentioning

confidence: 99%

Multistep and multitask Bax activation

Ghibelli

Diederich

2010

Mitochondrion

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“…Bax is the major proapoptotic Bcl2 family protein that is widely expressed in various human lung cancer cells including both small cell lung cancer and non-small cell lung cancer cells (11). Recent reports indicate that phosphorylation, a post-translational modification, can regulate the proapoptotic activity of Bax (11)(12)(13).…”

mentioning

confidence: 99%

“…Recent reports indicate that phosphorylation, a post-translational modification, can regulate the proapoptotic activity of Bax (11)(12)(13). The growth factor granulocyte/macrophage colony-stimulating factor and nicotine have been found to induce Bax phosphorylation at Ser-184 through a physiological Bax kinase AKT, which is associated with inactivation of the proapoptotic function of Bax and prolonged cell survival (11,12). However, whether a physiological phosphatase is involved in dephosphorylation of Bax remains unclear.…”

mentioning

confidence: 99%

Protein Phosphatase 2A Enhances the Proapoptotic Function of Bax through Dephosphorylation

Xin

Deng

2006

Journal of Biological Chemistry

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128

118

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Bax is a major proapoptotic member of the Bcl2 family that is required for apoptotic cell death. We have recently discovered that Bax phosphorylation at serine 184 induced by nicotine through activation of protein kinase AKT abolishes its proapoptotic function in human lung cancer cells. Here we found that either treatment of cells with the protein phosphatase 2A (PP2A) inhibitor okadaic acid or specific disruption of PP2A activity by expression of SV40 small tumor antigen enhanced Bax phosphorylation, whereas C 2 -ceramide, a potent PP2A activator, reduced nicotine-induced Bax phosphorylation, suggesting that PP2A may function as a physiological Bax phosphatase. PP2A co-localized and interacted with Bax. Purified, active PP2A directly dephosphorylated Bax in vitro. Overexpression of the PP2A catalytic subunit (PP2A/C) suppressed nicotine-stimulated Bax phosphorylation in association with increased apoptotic cell death. By contrast, depletion of PP2A/C by RNA interference enhanced Bax phosphorylation and prolonged cell survival. Mechanistically C 2 -ceramide-induced Bax dephosphorylation caused a conformational change by exposure of the 6A7 epitope (amino acids 13-19) that is normally hidden at its N terminus that promoted the insertion of Bax into mitochondrial membranes and formation of Bax oligomers leading to cytochrome c release and apoptosis. In addition, PP2A directly disrupted the Bcl2/Bax association to liberate Bax from the heterodimer complex. Thus, PP2A may function as a physiological Bax regulatory phosphatase that not only dephosphorylates Bax but also activates its proapoptotic function.Apoptosis occurs by activation of an intrinsic or extrinsic pathway and is largely regulated by the Bcl-2 family of apoptotic regulators that is comprised of three subfamilies (1-2). The subfamily including Bcl2, Bcl-XL, and MCL1 members block apoptosis, whereas the Bax subfamily, consisting of Bax and Bak, or the BH3 2 -only subfamily, including Bad, Bid, Bok, Bik, Bim, and PUMA, promote apoptosis (3-8). Bcl2 family members function in a tightly regulated network that protects or induces mitochondrial dysfunction. It is popularly held that antiapoptotic Bcl2 and Bcl-XL heterodimerize with proapoptotic Bax or Bak such that the hydrophobic crevices on their surfaces bind to the exposed BH3 domain of Bax or Bak to block their proapoptotic function. Thus, heterodimerization appears to regulate, at least in part, cell survival or death (5). Furthermore the BH3 domain of the proapoptotic members is required for both their oligomerization and killing activity, although homodimerization does not necessarily correlate with killing activity (9). Genetic studies using Bax and Bak single and double homozygous knock-out mice reveal that either Bax or Bak is essential for inducing mitochondrial dysfunction characterized by the release of potent caspase activators including cytochrome c (Cyt c) and Smac/Diablo that initiate the intrinsic pathway (10).Bax is the major proapoptotic Bcl2 family protein that is widely expressed in v...

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“…36) Activated PI3K/AKT could either increased Bcl-2 expression or directly phosphorylated and inactivated the proapoptotic function of Bax. 37,38) Therefore, we deduced that in our study, G-CSF increased Akt phosphorylation and the latter reduced Bax expression. Whether p53 played roles in the antiapoptotic effects elicited by G-CSF treatment still needed explored in our modle.…”

Section: Discussionmentioning

confidence: 92%

Granulocyte Colony-Stimulating Factor Treatment Prevents Cognitive Impairment Following Status Epilepticus in Rats

Zhang

Wang

Sun

et al. 2010

Biological & Pharmaceutical Bulletin

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Status epilepticus (SE) rendered selective neuronal loss and cognitive impairments. Previous studies proved that granulocyte colony-stimulating factor (G-CSF) acted as a neuroprotectant in some nervous diseases. However, no investigations were focused on whether G-CSF could protect the hippocampus from SE. In this study, we administered recombinant human G-CSF into Sprague-Dawley rats with lithium-pilocarpine-induced SE subcutaneously for three times. The Morris water maze was employed to determine spatial learning ability from the 15th to 20th days after the treatment. The quantitative terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate (dUTP) nick end labeling (TUNEL) staining and levels of apoptosis-related molecules including cleaved caspase-3, Bcl-xL and Bax on hippocampal CA1 region were examined by immunohistochemical staining at the 3rd and the 5th day after the treatment. Moreover, the phosphorylation of AKT was evaluated with Western blot at the 6th, 24th and 48th hours after the treatment to explore apoptosis and detect the protective effects of G-CSF. We found G-CSF treatment prevented SE-induced cognitive impairments with the decreased escape latency time on the 17th (29.86؎9.09 vs. 38.33؎6.94, pϽ Ͻ0.05) and 18th days (23.83؎6.17 vs. 33.52؎8.48, pϽ0.05). The reduced TUNEL staining demonstrated reduced neuronal apoptosis occurrences. The anti-apoptotic effects were associated with decreased cleaved caspase-3 and Bax expression and increased phosphorylation of AKT and Bcl-xL expression. Taken together, our results suggested that systemic G-CSF treatment conducted neuroprotective function following SE through an anti-apoptotic pathway and prevented cognitive impairments, which may provide novel insights into pathogenesis and treatment following SE injury.

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Nicotine Inactivation of the Proapoptotic Function of Bax through Phosphorylation

Cited by 210 publications

References 44 publications

Multistep and multitask Bax activation

Multistep and multitask Bax activation

Protein Phosphatase 2A Enhances the Proapoptotic Function of Bax through Dephosphorylation

Granulocyte Colony-Stimulating Factor Treatment Prevents Cognitive Impairment Following Status Epilepticus in Rats

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