Apoptosis or growth arrest: Modulation of tumor suppressor p53's specificity by bacterial redox protein azurin

Yamada, Tohru; Hiraoka, Yutaka; Ikehata, Masateru; Kimbara, Kazuhide; Avner, Benjamin S.; Gupta, Tapas K. Das; Chakrabarty, Ananda M.

doi:10.1073/pnas.0400899101

Cited by 91 publications

(91 citation statements)

References 31 publications

(62 reference statements)

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“…The p53 tumor suppressor protein is a transcription factor that is activated in response to TNF stimuli (14). Activation of p53 affects genes associated with cell cycle arrest, DNA repair, and apoptosis including p21 waf/cip1 (15,16), Bax (17), and Bcl-2 (18). She et al (19) report that extracellular signal-regulated kinase 1/2 (ERK1/2) mediate UVB-induced phosphorylation of mouse p53 at serine 15.…”

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confidence: 99%

Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Sensitizes Breast Cancer Cells to Tumor Necrosis Factor-α–Induced Apoptosis and Cell Growth Arrest

Wang

Li²,

Li³

et al. 2005

Clinical Cancer Research

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Purpose:The current therapeutic approach is not so effective in breast cancer patients. Alternative treatment protocols aimed at different targets need to be explored. We recently reported a novel phosphatidylethanolamine-binding protein, human phosphatidylethanolamine-binding protein 4 (hPEBP4), as an antiapoptotic molecule. The finding led us to explore a promising approach for breast cancer therapy via silencing the expression of hPEBP4. Experimental Design: hPEBP4 expression in clinical breast specimens was examined by Tissue Microarrays. RNA interference was used to silence hPEBP4 expression in MCF-7 breast carcinoma cells and the effects on cell proliferation, cell cycle progression, apoptosis, as well as underlying mechanisms, were investigated.Results: hPEBP4 was found to be expressed in up to 50% of breast cancers but in only <4% of normal breast tissues. Silencing of hPEBP4 potentiated tumor necrosis factor-a (TNF-a)î nduced apoptosis and cell cycle arrest in MCF-7 cells, which was due to the increased mitogen-activated protein kinase activation and the enhanced phosphatidylethanolamine externalization. Further investigation showed that silencing of hPEBP4 in MCF-7 cells promoted TNF-a-induced stability of p53, up-regulation of phospho-p53 ser15 , p21waf/cip , and Bax, and down-regulation of Bcl-2 and Bcl-xL, which were shown to depend on extracellular signalregulated kinase 1/2 and c-jun NH 2 -terminal kinase activation by hPEBP4 silencing. Moreover, the increased proportion of cells in the G 0 -G 1 phase of cell cycle was observed in hPEBP4-silenced MCF-7 cells on TNF-a treatment and the expression of cyclin A and cyclin E was down-regulated more significantly. Conclusions:The antiapoptotic effect and the preferential expression pattern in breast cancer tissues make hPEBP4 a new target for breast cancer therapy. Silencing of hPEBP4 expression may be a promising approach for the treatment of breast carcinoma.

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Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Sensitizes Breast Cancer Cells to Tumor Necrosis Factor-α–Induced Apoptosis and Cell Growth Arrest

Wang

Li²,

Li³

et al. 2005

Clinical Cancer Research

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“…This mutant triggered the inhibition of cell cycle progression in mammalian cells but little apoptosis. 46,48,59 The oligomerization domain of p53 is located in the central to the C-terminal region of p53; it might therefore be possible that the M44KM64E mutant azurin binds to p53 in this region and somehow directs the specificity of p53 for p21. p53 is a very well characterized molecule.…”

Section: Bacteria-derived Anti-cancer Agentsmentioning

confidence: 99%

Microbial based therapy of cancer: A new twist to an age old practice

Punj

Saint‐Dic²,

Daghfal³

et al. 2004

Cancer Biology & Therapy

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The use of bacteria in the regression of tumors has long been known. Various approaches for using bacteria in cancer therapy include the use of bacteria as sensitizing agents for chemotherapy, as delivery agents for cancer drugs and as agents for gene therapy. The tumor regression stimulated by infecting microorganisms has been attributed to activation of the immune system of the host. However, recent studies indicate that when tumorharboring mice with defective immune systems are infected with certain microorganisms, the regression of the tumor is still observed, suggesting that there are other host factors contributing to the microbial associated regression of tumors. Since the use of live or attenuated bacteria for tumor regression has associated toxic effects, studies are in progress to identify a pure microbial metabolite or any component of the microbial cell that might have anti-cancer activity. It has now been demonstrated that a redox protein from Pseudomonas aeruginosa, a cupredoxin, can enter into human cancer cells and trigger the apoptotic cell death. In vivo, this cupredoxin can lead to the regression of tumor growth in immunodeficient mice harboring xenografted melanomas and breast cancer tumors without inducing significant toxic effects, suggesting that it has potential anti-cancer activity. This bacterial protein interacts with p53 and modulates mammalian cellular activity. Hence, it could potentially be used as an anti-cancer agent for solid tumors and has translational value in tumor-targeted or in combinational-biochemotherapy strategies for cancer treatments. Here, we focus on diverse approaches to cancer biotherapy, including bacteriolytic and bacterially-derived anti-cancer agents with an emphasis on their mechanism of action and therapeutic potential.

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“…5 The complex formed by azurin and p53 as well as its electron transfer partner cytochrome c induces apoptosis in cancer cells through cell cycle arrest at the G1 phase or caspase-mediated mitochondrial cytochrome c release. 6,7 Azurin is therefore expected to be a potential drug for cancer therapy. 8,9 The precursor form of azurin (148 residues) produced by P. aeruginosa is converted to a mature form (Paz, 128 residues) through the release of a signal peptide (20 residues) across the inner membrane (Fig.…”

Section: Introductionmentioning

confidence: 99%

Structural studies on Laz, a promiscuous anticancer Neisserial protein

et al. 2015

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Azurin and Laz (lipidated azurin) are 2 bacterial proteins with anticancer, anti-viral and anti-parasitic activities. Azurin, isolated from the bacterium Pseudomonas aeruginosa, termed Paz, demonstrates anticancer activity against a range of cancers but not against brain tumors. In contrast, Laz is produced by members of Gonococci/Meningococci, including Neisseria meningitides which can cross the blood-brain barrier to infect brain meninges. It has been previously reported that Laz has an additional 39 amino acid moiety, called an H.8 epitope, in the N-terminal part of the azurin moiety that allows Laz to cross the entry barrier to brain tumors such as glioblastomas. Exactly, how the H.8 epitope helps the azurin moiety of Laz to cross the entry barriers to attack glioblastoma cells is unknown. In this paper, we describe the structural features of the H.8 moiety in Laz using X-ray crystallography and demonstrate that while the azurin moiety of Laz adopts a b-sandwich fold with 2 b-sheets arranged in the Greek key motif, the H.8 epitope was present as a disordered structure outside the Greek key motif. Structures of Paz and H.8 epitope-deficient Laz are well superimposed. The structural flexibility of the H.8 motif in Laz explains the extracellular location of Laz in Neisseria where it can bind the key components of brain tumor cells to disrupt their tight junctions and allow entry of Laz inside the tumors to exert cytotoxicity.

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Apoptosis or growth arrest: Modulation of tumor suppressor p53's specificity by bacterial redox protein azurin

Cited by 91 publications

References 31 publications

Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Sensitizes Breast Cancer Cells to Tumor Necrosis Factor-α–Induced Apoptosis and Cell Growth Arrest

Silencing of Human Phosphatidylethanolamine-Binding Protein 4 Sensitizes Breast Cancer Cells to Tumor Necrosis Factor-α–Induced Apoptosis and Cell Growth Arrest

Microbial based therapy of cancer: A new twist to an age old practice

Structural studies on Laz, a promiscuous anticancer Neisserial protein

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