The Experts below are selected from a list of 27918 Experts worldwide ranked by ideXlab platform
Karen H Vousden - One of the best experts on this subject based on the ideXlab platform.
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Contribution of membrane localization to the apoptotic activity of Puma
Apoptosis, 2008Co-Authors: Karen S. Yee, Karen H VousdenAbstract:The BH3-only protein Puma plays an important role in the activation of apoptosis in response to p53. In different studies, Puma has been described to function by either directly activating the pro-apoptotic proteins Bax and Bak, or by neutralizing anti-apoptotic members of the Bcl2 family. We have examined the contribution of regions of Puma other than the BH3 domain to its localization and function. Although the hydrophobic domain in the C-terminus of Puma is necessary for efficient mitochondrial localization of Puma itself, Puma proteins lacking this region can still induce apoptosis and localize to the mitochondria through binding to Bcl2. Even a nuclear localization signal (NLS)-tagged Puma protein retains apoptotic activity and can be efficiently relocalized from the nucleus after interaction with ectopically expressed Bcl2, underscoring the efficiency of this interaction. Interestingly, unlike the Bcl2 interaction, the binding of Puma to Bax is severely compromised by the loss of the C-terminal domain of Puma. However, since the loss of the C-terminus does not compromise the ability of Puma to induce cell death, our results indicate that the key apoptotic function of Puma is through interaction with anti-apoptotic proteins such as Bcl2.
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Puma a novel proapoptotic gene is induced by p53
Molecular Cell, 2001Co-Authors: Katsunori Nakano, Karen H VousdenAbstract:Abstract The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named Puma ( p 53 u pregulated m odulator of a poptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins (Puma-α and Puma-β) that are induced in cells following p53 activation. Puma-α and Puma-β show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of Puma expression reduced the apoptotic response to p53, and Puma is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway.
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Puma, a novel proapoptotic gene, is induced by p53.
Molecular cell, 2001Co-Authors: Katsunori Nakano, Karen H VousdenAbstract:The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named Puma (p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain-containing proteins (Puma-alpha and Puma-beta) that are induced in cells following p53 activation. Puma-alpha and Puma-beta show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of Puma expression reduced the apoptotic response to p53, and Puma is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway.
Lin Zhang - One of the best experts on this subject based on the ideXlab platform.
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Puma Suppresses Intestinal Tumorigenesis in Mice
Cancer research, 2009Co-Authors: Wei Qiu, Eleanor B. Carson-walter, Shih Fan Kuan, Lin ZhangAbstract:Defective apoptosis contributes to tumorigenesis, although the critical molecular targets remain to be fully characterized. Puma, a BH3-only protein essential for p53-dependent apoptosis, has been shown to suppress lymphomagenesis. In this study, we investigated the role of Puma in intestinal tumorigenesis using two animal models. In the azoxymethane (AOM)/dextran sulfate sodium salt model, Puma deficiency increased the multiplicity and size of colon tumors but reduced the frequency of β-catenin hotspot mutations. The absence of Puma led to a significantly elevated incidence of precursor lesions induced by AOM. AOM was found to induce p53-dependent Puma expression and Puma-dependent apoptosis in the colonic crypts and stem cell compartment. Furthermore, Puma deficiency significantly enhanced the formation of spontaneous macroadenomas and microadenomas in the distal small intestine and colon of APC Min/+ mice. These results show an essential role of Puma-mediated apoptosis in suppressing intestinal tumorigenesis in mice. [Cancer Res 2009;69(12):4999–5006]
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Sp1 and p73 activate Puma following serum starvation.
Carcinogenesis, 2008Co-Authors: Lihua Ming, Wen Yue, Tsukasa Sakaida, Anupma Jha, Lin ZhangAbstract:p53-upregulated modulator of apoptosis (Puma) plays an essential role in p53-dependent apoptosis following DNA damage. Puma also mediates apoptosis independent of p53. In this study, we investigated the role and mechanism of Puma induction in response to serum starvation in p53-deficient cancer cells. Following serum starvation, the binding of Sp1 to the Puma promoter significantly increased, whereas inhibition of Sp1 completely abrogated Puma induction. p73 was found to be upregulated by serum starvation and mediate Puma induction through the p53-binding sites in the Puma promoter. Sp1 and p73β appeared to cooperatively activate Puma transcription, which is inhibited by the phosphoinsitide 3-kinase (PI3K)-protein kinase B (AKT) pathway. Furthermore, knockdown of Puma suppressed serum starvation-induced apoptosis in leukemia cells. Our results suggest that transcription factors Sp1 and p73 mediate p53-independent induction of Puma following serum starvation to trigger apoptosis in human cancer cells.
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Selection against Puma gene expression in Myc-driven B-cell lymphomagenesis.
Molecular and cellular biology, 2008Co-Authors: Sean P. Garrison, John R. Jeffers, Chunying Yang, Jonas Nilsson, Mark A. Hall, Jerold E. Rehg, Wen Yue, Lin Zhang, Mihaela OnciuAbstract:The p53 tumor suppressor pathway limits oncogenesis by inducing cell cycle arrest or apoptosis. A key p53 target gene is Puma, which encodes a BH3-only proapoptotic protein. Here we demonstrate that Puma deletion in the Emu-Myc mouse model of Burkitt lymphoma accelerates lymphomagenesis and that approximately 75% of Emu-Myc lymphomas naturally select against Puma protein expression. Furthermore, approximately 40% of primary human Burkitt lymphomas fail to express detectable levels of Puma and in some tumors this is associated with DNA methylation. Burkitt lymphoma cell lines phenocopy the primary tumors with respect to DNA methylation and diminished Puma expression, which can be reactivated following inhibition of DNA methyltransferases. These findings establish that Puma is silenced in human malignancies, and they suggest Puma as a target for the development of novel chemotherapeutics.
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Puma dissociates bax and bcl xl to induce apoptosis in colon cancer cells
Journal of Biological Chemistry, 2006Co-Authors: Lihua Ming, Peng Wang, Alexander Bank, Lin ZhangAbstract:Puma is a BH3-only Bcl-2 family protein that plays an essential role in DNA damage-induced apoptosis. Puma interacts with anti-apoptotic Bcl-2 and Bcl-XL and is dependent on Bax to induce apoptosis. In this study, we investigated how the interactions of Puma with the antiapoptotic proteins coordinate with Bax to initiate apoptosis in HCT116 colon cancer cells. We found that Bcl-XL was most effective among several antiapoptotic proteins in suppressing Puma-induced apoptosis and Puma-dependent apoptosis induced by the DNA-damaging agent adriamycin. Mutant Bcl-XL that cannot interact with Bax was unable to protect cells from Puma-mediated apoptosis. Knockdown of Bcl-XL by RNA interference significantly enhanced Puma-mediated apoptosis in HCT116 cells but not in Puma-knockout cells. Furthermore, Bax was found to be dissociated preferentially from Bcl-XL in HCT116 cells but not in the Puma-knockout cells, in response to Puma induction and adriamycin treatment. Puma inhibited the association of Bax and Bcl-XL in vitro by directly binding to Bcl-XL through its BH3 domain. Finally, we found that wild-type Bax, but not mutant Bax deficient in either multimerization or mitochondrial localization, was able to restore Puma-induced apoptosis in the BAX-knockout cells. Together, these results indicate that Puma initiates apoptosis in part by dissociating Bax and Bcl-XL, thereby promoting Bax multimerization and mitochondrial translocation.
Katsunori Nakano - One of the best experts on this subject based on the ideXlab platform.
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Puma a novel proapoptotic gene is induced by p53
Molecular Cell, 2001Co-Authors: Katsunori Nakano, Karen H VousdenAbstract:Abstract The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named Puma ( p 53 u pregulated m odulator of a poptosis) as a target for activation by p53. This gene encodes two BH3 domain–containing proteins (Puma-α and Puma-β) that are induced in cells following p53 activation. Puma-α and Puma-β show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of Puma expression reduced the apoptotic response to p53, and Puma is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1–dependent pathway.
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Puma, a novel proapoptotic gene, is induced by p53.
Molecular cell, 2001Co-Authors: Katsunori Nakano, Karen H VousdenAbstract:The p53 tumor-suppressor protein functions as a transcriptional activator, and several p53-inducible genes that play a role in the induction of apoptosis in response to p53 have been described. We have identified a novel gene named Puma (p53 upregulated modulator of apoptosis) as a target for activation by p53. This gene encodes two BH3 domain-containing proteins (Puma-alpha and Puma-beta) that are induced in cells following p53 activation. Puma-alpha and Puma-beta show similar activities; they bind to Bcl-2, localize to the mitochondria to induce cytochrome c release, and activate the rapid induction of programmed cell death. Antisense inhibition of Puma expression reduced the apoptotic response to p53, and Puma is likely to play a role in mediating p53-induced cell death through the cytochrome c/Apaf-1-dependent pathway.
Kou-gi Shyu - One of the best experts on this subject based on the ideXlab platform.
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Regulation of Puma induced by mechanical stress in rat cardiomyocytes
Journal of biomedical science, 2012Co-Authors: Wen Pin Cheng, Bao Wei Wang, Kou-gi ShyuAbstract:Puma (p53-up-regulated modulator of apoptosis), an apoptosis regulated gene, increased during endoplasmic reticulum stress. However, the expression of Puma in cardiomyocytes under mechanical stress is little known. We aimed to investigate the regulation mechanism of Puma expression and apoptosis induced by mechanical stress in cardiomyocytes. Aorta-caval (AV) shunt was performed in adult Wistar rats to induce volume overload. Rat neonatal cardiomyocytes were stretched by vacuum to 20% of maximum elongation at 60 cycles/min. Puma protein and mRNA were up-regulated in the shunt group as compared with sham group. The increased Puma protein expression and apoptosis induced by shunt was reversed by treatment with atorvastatin at 30 mg/kg/ day orally for 7 days. TUNEL assay showed that treatment with atorvastatin inhibited the apoptosis induced by volume overload. Cyclic stretch significantly enhanced Puma protein and gene expression. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125, JNK small interfering RNA (siRNA) and interferon-γ (INF-γ) antibody 30 min before stretch reduced the induction of Puma protein. Gel shift assay demonstrated that stretch increased the DNA binding activity of interferon regulatory factor-1. Stretch increased, while Puma-Mut plasmid, SP600125 and INF-γ antibody abolished the Puma promoter activity induced by stretch. Puma mediated apoptosis induced by stretch was reversed by Puma siRNA and atorvastatin. Mechanical stress enhanced apoptosis and Puma expression in cardiomyocytes. Treatment with atorvastatin reversed both Puma expression and apoptosis induced by mechanical stress in cardiomyocytes.
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Mechanical stretch induces the apoptosis regulator Puma in vascular smooth muscle cells.
Cardiovascular research, 2011Co-Authors: Wen Pin Cheng, Bao Wei Wang, Shih-chung Chen, Hang Chang, Kou-gi ShyuAbstract:Aims The expression of Puma (p53-up-regulated modulator of apoptosis), an apoptosis-regulating gene, increases during endoplasmic reticulum stress. The mechanisms by which cyclic stretch influences the regulation of Puma in vascular smooth muscle cells (VSMCs) during apoptosis remain unclear. We hypothesized that cyclic stretch enhances Puma expression in VSMCs undergoing apoptosis. Methods and results Human VSMCs grown on a Flexcell I flexible membrane base were stretched via vacuum to 20% of elongation at a frequency of 1 Hz. An in vivo model of volume overload with aorta-caval shunt and pressure overload with aortic banding in adult rats was used to study Puma expression. Cyclic stretch markedly enhanced Puma protein and gene expression after stretch. Addition of c-jun N-terminal kinase (JNK) inhibitor SP600125 and interferon-γ (IFN-γ) antibody 30 min before stretch inhibited Puma expression. Gel shift assay demonstrated that stretch increased the DNA binding activity of interferon regulatory factor-1 (IRF-1). SP600125, JNK small interfering RNA, and IFN-γ antibody attenuated the DNA binding activity induced by stretch. Puma-Mut plasmid, SP600125, and IRF-1 antibody attenuated the promoter activity. Stretch increased secretion of IFN-γ from VSMCs, and conditioned media from stretched VSMCs increased Puma protein expression. The in vivo model of aorta-caval shunt and aortic banding also showed increased Puma protein expression in the aorta. Conclusion Cyclic mechanical stretch increases Puma expression in cultured human VSMCs. The Puma expression induced by stretch is mediated by IFN-γ, JNK, and IRF-1 pathways. These findings suggest that Puma is an important mediator in VSMC apoptosis induced by stretch.
James N Ihle - One of the best experts on this subject based on the ideXlab platform.
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Puma is an essential mediator of p53 dependent and independent apoptotic pathways
Cancer Cell, 2003Co-Authors: John R. Jeffers, Chunying Yang, Evan Parganas, Jinling Wang, Jennifer Brennan, Kirsteen H Maclean, Thomas Chittenden, James N IhleAbstract:Abstract Puma encodes a BH3-only protein that is induced by the p53 tumor suppressor and other apoptotic stimuli. To assess its physiological role in apoptosis, we generated Puma knockout mice by gene targeting. Here we report that Puma is essential for hematopoietic cell death triggered by ionizing radiation (IR), deregulated c-Myc expression, and cytokine withdrawal. Puma is also required for IR-induced death throughout the developing nervous system and accounts for nearly all of the apoptotic activity attributed to p53 under these conditions. These findings establish Puma as a principal mediator of cell death in response to diverse apoptotic signals, implicating Puma as a likely tumor suppressor.
