Bax conformational change is a crucial step for PUMA-mediated apoptosis in human leukemia

Liu, Fengting; Newland, Adrian C.; Li, Jia

doi:10.1016/j.bbrc.2003.09.109

Cited by 77 publications

(62 citation statements)

References 41 publications

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“…PUMA, a mitochondrial membrane protein, induces apoptosis by translocating functional BAX complexes onto the mitochondrial outer membrane (26,47). We found that BAX-inhibiting peptide not only blocks formation of functional BAX on the mitochondrial membrane but also greatly (>90%) inhibited the generation of ROS in PUMAoverexpressing cells.…”

Section: Discussionmentioning

confidence: 85%

PUMA Overexpression Induces Reactive Oxygen Species Generation and Proteasome-Mediated Stathmin Degradation in Colorectal Cancer Cells

et al. 2005

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Increased amounts of reactive oxygen species (ROS) induce apoptosis in mammalian cells. PUMA (P53 up-regulated modulator of apoptosis), a mitochondrial proapoptotic BH3-only protein, induces rapid apoptosis through a Bax-and mitochondria-dependent pathway. However, the molecular basis of PUMA-induced apoptosis is largely not understood. Using a combination of biophysical and biochemical methods and PUMA-inducible colorectal cells, DLD-1.PUMA, we showed that (a) PUMA-induced apoptosis is dose and time dependent; (b) PUMA-induced apoptosis is directly associated with ROS generation; (c) diphenyleneiodonium chloride, a ROS blocker, or BAX-inhibiting peptide, a suppressor of BAX translocation, decreased ROS generation and apoptosis in DLD-1.PUMA cells; (d) overexpression of PUMA induced up-regulation (>1.34-fold) of peroxiredoxin 1 and down-regulation (by 25%) of stathmin through proteasome-mediated degradation; and (e) hydrogen peroxide down-regulated stathmin and disrupted the cellular microtubule network. Our findings indicate that PUMA induces apoptosis, in part, through the BAX-dependent generation of superoxide and hydrogen peroxide. ROS overproduction and oxidative stress induce proteome-wise alterations, such as stathmin degradation and disorganization of the cell microtubule network, in apoptotic cells. (Cancer Res 2005; 65(5): 1647-54)

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Section: Discussionmentioning

confidence: 85%

PUMA Overexpression Induces Reactive Oxygen Species Generation and Proteasome-Mediated Stathmin Degradation in Colorectal Cancer Cells

et al. 2005

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“…Recent data implicate Bax as an important mediator of PUMA-activated apoptotic signaling (30,32). The BH3 domain of PUMA specifically interacts with the first ␣ helix of Bax, which leads to Bax activation (33).…”

Section: Resultsmentioning

confidence: 99%

Full-length p73α Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells

Nyman

Sobczak-Pluta

Vlachos

et al. 2005

Journal of Biological Chemistry

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The p73 gene, a member of the p53 family, encodes several variants through differential splicing and use of alternative promoters. At the NH 2 terminus, two different promoters generate the fulllength and the ⌬N isoforms, with or without the transactivating domain. At the COOH terminus, seven isoforms generated through alternative splicing have been cloned. Previous studies have demonstrated that ⌬Np73 isoforms exert a dominant-negative effect on p73 by blocking their transactivation activity and hence the ability to induce apoptosis. Considerable efforts are made to identify the functional diversity of the COOH-terminal p73 variants. In this study, we found that p73␣ inhibited drug-induced apoptosis in small cell lung carcinoma cells, whereas p73␤ promoted it. p73␣ prevented Bax activation, mitochondrial dysfunction, and caspase activation. In addition, p73␣ was also able to reduce apoptosis induced by the BH3-only protein PUMA (p53 up-regulated modulator of apoptosis). Furthermore, we discovered that p73␣ is able to inhibit the pro-apoptotic effect of p73␤, demonstrating the existence of equilibrium between these two p73 isoforms. In conclusion, the reported overexpression of p73␣ in certain tumor types, and our findings that p73␣ exerts anti-apoptotic functions, indicate a potential oncogenic activity for p73.

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“…These studies have reported that PUMA binds to the first helix of Bax and triggers a conformational modification of Bax, resulting in its accumulation on the mitochondria and inducing the release of cytochrome c to activate the final steps of pcd. 15,18,19 These reports argue that the current 'dogma,' that is, that BH3-only proteins such as PUMA act as antagonists of antiapoptotic Bcl-2 family members such as Bcl-xL 34,35 but not as direct interactors with Bax or Bak, may turn out to be an overly simplistic model, and that, instead, at least some of these proteins may interact with Bax (or with both Bax and Bcl-2). Similarly, Reimertz et al 15 recently demonstrated colocalization of Bax and PUMA in SH-SY5Y cells during activation of the mitochondrial apoptotic pathway triggered by tunicamycin.…”

Section: Discussionmentioning

confidence: 99%

“…Membranes were probed with anti-PUMA antibody, anti-P53 antibody and anti-GAPDH antibody steps of pcd. 15,18 BH3-only proteins like PUMA and Bid have been shown to interact with the first helix of Bax, induce a change in its conformation and stimulate its mitochondrial activity leading to apoptotic cell death. 19 ER stress inducers also trigger the Bax conformational change and mitochondrial translocation, leading to the release of Smac and Omi and activation of pcd.…”

Section: Interaction Of P23 Puma and Baxmentioning

confidence: 99%

Coupling endoplasmic reticulum stress to the cell-death program: a novel HSP90-independent role for the small chaperone protein p23

et al. 2005

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The endoplasmic reticulum (ER) is the principal organelle for the biosynthesis of proteins, steroids and many lipids, and is highly sensitive to alterations in its environment. Perturbation of Ca 2 þ homeostasis, elevated secretory protein synthesis, deprivation of glucose or other sugars, altered glycosylation and/or the accumulation of misfolded proteins may all result in ER stress, and prolonged ER stress triggers cell death. Studies from multiple laboratories have identified the roles of several ER stress-induced cell-death modulators and effectors through the use of biochemical, pharmacological and genetic tools. In the present work, we describe the role of p23, a small chaperone protein, in preventing ER stress-induced cell death. p23 is a highly conserved chaperone protein that modulates HSP90 activity and is also a component of the steroid receptors. p23 is cleaved during ER stress-induced cell death; this cleavage, which occurs close to the carboxy-terminus, requires caspase-3 and/or caspase-7, but not caspase-8. Blockage of the caspase cleavage site of p23 was associated with decreased cell death induced by ER stress. Immunodepletion of p23 or inhibition of p23 expression by siRNA resulted in enhancement of ER stress-induced cell death. While p23 co-immunoprecipitated with the BH3-only protein PUMA (p53-upregulated modulator of apoptosis) in untreated cells, prolonged ER stress disrupted this interaction. The results define a protective role for p23, and provide further support for a model in which ER stress is coupled to the mitochondrial intrinsic apoptotic pathway through the activities of BH3 family proteins.

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Bax conformational change is a crucial step for PUMA-mediated apoptosis in human leukemia

Cited by 77 publications

References 41 publications

PUMA Overexpression Induces Reactive Oxygen Species Generation and Proteasome-Mediated Stathmin Degradation in Colorectal Cancer Cells

PUMA Overexpression Induces Reactive Oxygen Species Generation and Proteasome-Mediated Stathmin Degradation in Colorectal Cancer Cells

Full-length p73α Represses Drug-induced Apoptosis in Small Cell Lung Carcinoma Cells

Coupling endoplasmic reticulum stress to the cell-death program: a novel HSP90-independent role for the small chaperone protein p23

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