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Anning Lin - One of the best experts on this subject based on the ideXlab platform.
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the bh3 only Protein BAD mediates tnfα cytotoxicity despite concurrent activation of ikk and nf κb in septic shock
Cell Research, 2018Co-Authors: Anning Lin, Jialing Xiang, Jie Yan, Hao Zhang, Yu Zhao, Xiang Yuan, Beicheng SunAbstract:The inflammatory cytokine TNFα plays a crucial role in the pathology of many inflammatory and infectious diseases. However, the mechanism underlying TNFα cytotoxicity in these diseases is incompletely understood. Here we report that the pro-apoptotic BCL-2 family member BAD mediates TNFα cytotoxicity despite concurrent activation of IKK and NF-κB in vitro by inducing apoptosis in cultured cells and in vivo by eliciting tissue damage of multiple organs and contributing to mortality in septic shock. At high doses, TNFα significantly inactivates RhoA through activation of the Src-p190GAP pathway, resulting in massive actin stress fiber destabilization, followed by substantial BAD release from the cytoskeleton to the cytosol. Under this condition, activated IKK fails to phosphorylate all cytosolic BAD, allowing translocation of non-phosphorylated BAD to mitochondria to trigger apoptosis. Polymicrobial infection utilizes the same mechanism as high-dose TNFα to elicit apoptosis-associated tissue damage of multiple organs. Consequently, loss of BAD or elimination of BAD pro-apoptotic activity protects mice from tissue damage of multiple organs and reduces mortality rates. Our results support a model in which BAD mediates TNFα cytotoxicity despite concurrent activation of the IKK-NF-κB pathway in cultured mammalian cells and in septic shock.
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Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation.
Cell, 2013Co-Authors: Jie Yan, Jing Liu, Jiyan Zhang, Jialing Xiang, Hao Zhang, Nika N. Danial, Yutin Lin, Jisheng Sun, Anning LinAbstract:The IκB kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The prosurvival function of IKK centers on activation of the transcription factor NF-κB, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here, we report that inactivation of the BH3-only Protein BAD by IKK independently of NF-κB activation suppresses TNFα-induced apoptosis. TNFα-treated Ikkβ(-/-) mouse embryonic fibroblasts (MEFs) undergo apoptosis significantly faster than MEFs deficient in both RelA and cRel due to lack of inhibition of BAD by IKK. IKK phosphorylates BAD at serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26 phosphorylation promotes BAD proapoptotic activity, thereby accelerating TNFα-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNFα-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-κB and inactivation of the proapoptotic BH3-only BAD Protein.
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Phosphorylation of Bcl-associated death Protein (BAD) by erythropoietin-activated c-Jun N-terminal Protein kinase 1 contributes to survival of erythropoietin-dependent cells
The international journal of biochemistry & cell biology, 2010Co-Authors: Hongbin Deng, Jingpu Zhang, Taewon Yoon, Dan-qing Song, Anning LinAbstract:The glycoProtein erythropoietin (Epo) is a hematopoietic cytokine necessary for the survival of erythrocytes from immature erythroid cells. The mitogen-activated c-Jun N-terminal kinase 1 (JNK1) plays an important role in the proliferation and survival of erythroid cells in response to Epo. However, the precise mechanism of JNK1 activation promoting erythroid cell survival is incompletely understood. Here, we reported that JNK1 is required for Epo-mediated cell survival through phosphorylation and inactivation of the pro-apoptotic, Bcl-2 homology domain 3 (BH3)-only Bcl-associated death Protein (BAD). Upon Epo withdrawal, HCD57 cells, a murine Epo-dependent cell line, displayed increased apoptotic cell death that was associated with decreased JNK1 activity. Epo withdrawal-induced apoptosis was promoted by inhibition of JNK1 activity but suppressed by expression of a constitutively active JNK1. Furthermore, Epo-activated JNK1 phosphorylated BAD at threonine 201, thereby inhibiting the association of BAD with the anti-apoptotic molecule B-cell lymphoma-extra large (Bcl-X(L)). Replacement of threonine 201 by alanine in BAD promoted Epo withdrawal-induced apoptosis. Thus, our results provide a molecular mechanism by which JNK1 contributes to the survival of erythroid cells.
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phosphorylation of BAD at thr 201 by jnk1 promotes glycolysis through activation of phosphofructokinase 1
Journal of Biological Chemistry, 2008Co-Authors: Hongbin Deng, Jialing Xiang, Jianqun Chen, Yingming Zhao, Anning LinAbstract:The mitogen-activated Protein kinase JNK1 suppresses interleukin-3 withdrawal-induced cell death through phosphorylation of the BH3-only pro-apoptotic Bcl-2 family Protein BAD at Thr-201. It is unknown whether JNK1 regulates glycolysis, an important metabolic process that is involved in cell survival, and if so, whether the regulation depends on Thr-201 phosphorylation of BAD. Here we report that phosphorylation of BAD by JNK1 is required for glycolysis through activation of phosphofructokinase-1 (PFK-1), one of the key enzymes that catalyze glycolysis. Genetic disruption of Jnk1 alleles or silencing of Jnk1 by small interfering RNA abrogates glycolysis induced by growth/survival factors such as serum or interleukin-3. Proteomic analysis identifies PFK-1 as a novel BAD-associated Protein. Although the interaction between PFK-1 and BAD is independent of JNK1, Thr-201 phosphorylation of BAD by JNK1 is required for PFK-1 activation. Thus, our results provide a novel molecular mechanism by which JNK1 promotes glycolysis for cell survival.
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BAD Ser128 is not phosphorylated by c-Jun NH2- terminal kinase for promoting apoptosis
Cancer research, 2005Co-Authors: Jiyan Zhang, Jing Liu, Anning LinAbstract:The phosphorylation and regulation of the proapoptotic Bcl-2 family Protein BAD by c-Jun NH2-terminal kinase (JNK) is controversial. JNK can suppress interleukin-3 withdrawal-induced apoptosis via phosphorylation of BAD at Thr201. However, it has also been reported that JNK promotes apoptosis through phosphorylation of BAD at Ser128. Here, we report that JNK is not a BAD Ser128 kinase. JNK phosphorylates murine BAD (mBAD), but not human BAD (hBAD), in which Ser91 is equivalent to Ser128 in mBAD. In contrast, Cdc2, which phosphorylates Ser128, phosphorylates both mBAD and hBAD. Replacement of Ser128 by alanine has no effects on BAD phosphorylation by JNK in vitro and in vivo. Two-dimensional phosphopeptide mapping in combination with phosphoamino acid analysis reveals that JNK does not phosphorylate BAD at Ser128. Elimination of Ser128 phosphorylation has no effects on the proapoptotic activity of BAD in apoptosis induced by UV via JNK or growth factor withdrawal. Thus, our results show that Ser128 is not phosphorylated by JNK for promoting cell death.
Audrey Minden - One of the best experts on this subject based on the ideXlab platform.
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Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4.
Molecular and cellular biology, 2003Co-Authors: Nerina Gnesutta, Audrey MindenAbstract:Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling Proteins regulate apoptosis, or programmed cell death, other Proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic Protein BAD. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK Proteins and suggests a new mechanism by which these Proteins promote cell survival.
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the serine threonine kinase pak4 prevents caspase activation and protects cells from apoptosis
Journal of Biological Chemistry, 2001Co-Authors: Nerina Gnesutta, Audrey MindenAbstract:Abstract The serine/threonine kinase PAK4 was identified first as an effector molecule for the Rho GTPase Cdc42. PAK4 differs from other members of the PAK family both in sequence and function. Previously we have shown that an important function of this kinase is to mediate the induction of filopodia in response to activated Cdc42. Studies with a constitutively active PAK4 mutant have shown that it also has a role in promoting anchorage-independent growth, an important hallmark of oncogenic transformation. Here we show that another function of PAK4 is to protect cells against apoptotic cell death. Expression of wild-type or constitutively active PAK4 delays the onset of apoptosis in response to tumor necrosis factor α stimulation, UV irradiation, and serum starvation. Consistent with an antiapoptotic function, expression of PAK4 leads to an increase in phosphorylation of the proapoptotic Protein BAD and an inhibition of caspase activation.
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The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis.
The Journal of biological chemistry, 2001Co-Authors: Nerina Gnesutta, Audrey MindenAbstract:Abstract The serine/threonine kinase PAK4 was identified first as an effector molecule for the Rho GTPase Cdc42. PAK4 differs from other members of the PAK family both in sequence and function. Previously we have shown that an important function of this kinase is to mediate the induction of filopodia in response to activated Cdc42. Studies with a constitutively active PAK4 mutant have shown that it also has a role in promoting anchorage-independent growth, an important hallmark of oncogenic transformation. Here we show that another function of PAK4 is to protect cells against apoptotic cell death. Expression of wild-type or constitutively active PAK4 delays the onset of apoptosis in response to tumor necrosis factor α stimulation, UV irradiation, and serum starvation. Consistent with an antiapoptotic function, expression of PAK4 leads to an increase in phosphorylation of the proapoptotic Protein BAD and an inhibition of caspase activation.
Nerina Gnesutta - One of the best experts on this subject based on the ideXlab platform.
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Death receptor-induced activation of initiator caspase 8 is antagonized by serine/threonine kinase PAK4.
Molecular and cellular biology, 2003Co-Authors: Nerina Gnesutta, Audrey MindenAbstract:Normal cell growth requires a precisely controlled balance between cell death and survival. This involves activation of different types of intracellular signaling cascades within the cell. While some types of signaling Proteins regulate apoptosis, or programmed cell death, other Proteins within the cell can promote survival. The serine/threonine kinase PAK4 can protect cells from apoptosis in response to several different types of stimuli. As is the case for other members of the p21-activated kinase (PAK) family, one way that PAK4 may promote cell survival is by phosphorylating and thereby inhibiting the proapoptotic Protein BAD. This leads in turn to the inhibition of effector caspases such as caspase 3. Here we show that in response to cytokines which activate death domain-containing receptors, such as the tumor necrosis factor and Fas receptors, PAK4 can inhibit the death signal by a different mechanism. Under these conditions, PAK4 inhibits apoptosis early in the caspase cascade, antagonizing the activation of initiator caspase 8. This inhibition, which does not require PAK4's kinase activity, may involve inhibition of caspase 8 recruitment to the death domain receptors. This role in regulating initiator caspases is an entirely novel role for the PAK Proteins and suggests a new mechanism by which these Proteins promote cell survival.
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the serine threonine kinase pak4 prevents caspase activation and protects cells from apoptosis
Journal of Biological Chemistry, 2001Co-Authors: Nerina Gnesutta, Audrey MindenAbstract:Abstract The serine/threonine kinase PAK4 was identified first as an effector molecule for the Rho GTPase Cdc42. PAK4 differs from other members of the PAK family both in sequence and function. Previously we have shown that an important function of this kinase is to mediate the induction of filopodia in response to activated Cdc42. Studies with a constitutively active PAK4 mutant have shown that it also has a role in promoting anchorage-independent growth, an important hallmark of oncogenic transformation. Here we show that another function of PAK4 is to protect cells against apoptotic cell death. Expression of wild-type or constitutively active PAK4 delays the onset of apoptosis in response to tumor necrosis factor α stimulation, UV irradiation, and serum starvation. Consistent with an antiapoptotic function, expression of PAK4 leads to an increase in phosphorylation of the proapoptotic Protein BAD and an inhibition of caspase activation.
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The serine/threonine kinase PAK4 prevents caspase activation and protects cells from apoptosis.
The Journal of biological chemistry, 2001Co-Authors: Nerina Gnesutta, Audrey MindenAbstract:Abstract The serine/threonine kinase PAK4 was identified first as an effector molecule for the Rho GTPase Cdc42. PAK4 differs from other members of the PAK family both in sequence and function. Previously we have shown that an important function of this kinase is to mediate the induction of filopodia in response to activated Cdc42. Studies with a constitutively active PAK4 mutant have shown that it also has a role in promoting anchorage-independent growth, an important hallmark of oncogenic transformation. Here we show that another function of PAK4 is to protect cells against apoptotic cell death. Expression of wild-type or constitutively active PAK4 delays the onset of apoptosis in response to tumor necrosis factor α stimulation, UV irradiation, and serum starvation. Consistent with an antiapoptotic function, expression of PAK4 leads to an increase in phosphorylation of the proapoptotic Protein BAD and an inhibition of caspase activation.
Jing Liu - One of the best experts on this subject based on the ideXlab platform.
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Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation.
Cell, 2013Co-Authors: Jie Yan, Jing Liu, Jiyan Zhang, Jialing Xiang, Hao Zhang, Nika N. Danial, Yutin Lin, Jisheng Sun, Anning LinAbstract:The IκB kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The prosurvival function of IKK centers on activation of the transcription factor NF-κB, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here, we report that inactivation of the BH3-only Protein BAD by IKK independently of NF-κB activation suppresses TNFα-induced apoptosis. TNFα-treated Ikkβ(-/-) mouse embryonic fibroblasts (MEFs) undergo apoptosis significantly faster than MEFs deficient in both RelA and cRel due to lack of inhibition of BAD by IKK. IKK phosphorylates BAD at serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26 phosphorylation promotes BAD proapoptotic activity, thereby accelerating TNFα-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNFα-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-κB and inactivation of the proapoptotic BH3-only BAD Protein.
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BAD Ser128 is not phosphorylated by c-Jun NH2- terminal kinase for promoting apoptosis
Cancer research, 2005Co-Authors: Jiyan Zhang, Jing Liu, Anning LinAbstract:The phosphorylation and regulation of the proapoptotic Bcl-2 family Protein BAD by c-Jun NH2-terminal kinase (JNK) is controversial. JNK can suppress interleukin-3 withdrawal-induced apoptosis via phosphorylation of BAD at Thr201. However, it has also been reported that JNK promotes apoptosis through phosphorylation of BAD at Ser128. Here, we report that JNK is not a BAD Ser128 kinase. JNK phosphorylates murine BAD (mBAD), but not human BAD (hBAD), in which Ser91 is equivalent to Ser128 in mBAD. In contrast, Cdc2, which phosphorylates Ser128, phosphorylates both mBAD and hBAD. Replacement of Ser128 by alanine has no effects on BAD phosphorylation by JNK in vitro and in vivo. Two-dimensional phosphopeptide mapping in combination with phosphoamino acid analysis reveals that JNK does not phosphorylate BAD at Ser128. Elimination of Ser128 phosphorylation has no effects on the proapoptotic activity of BAD in apoptosis induced by UV via JNK or growth factor withdrawal. Thus, our results show that Ser128 is not phosphorylated by JNK for promoting cell death.
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Role of JNK activation in apoptosis: A double-edged sword
Cell Research, 2005Co-Authors: Jing Liu, Anning LinAbstract:JNK is a key regulator of many cellular events, including programmed cell death (apoptosis). In the absence of NF-kB activation, prolonged JNK activation contributes to TNF-a induced apoptosis. JNK is also essential for UV induced apoptosis. However, recent studies reveal that JNK can suppress apoptosis in IL-3-dependent hematopoietic cells via phosphorylation of the proapoptotic Bcl-2 family Protein BAD. Thus, JNK has pro- or antiapoptotic functions, depending on cell type, nature of the death stimulus, duration of its activation and the activity of other signaling pathways.
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JNK Suppresses Apoptosis via Phosphorylation of the Proapoptotic Bcl-2 Family Protein BAD
Molecular cell, 2004Co-Authors: Yuzuru Minemoto, Jing Liu, Jiyan Zhang, Fangming Tang, Truc N. Bui, Jialing Xiang, Anning LinAbstract:JNK has been suggested to be proapoptotic, antiapoptotic, or have no role in apoptosis depending on the cell type and stimulus used. The precise mechanism of JNK action, under conditions when it promotes cell survival, is not entirely clear. Here, we report that JNK is required for IL-3-mediated cell survival through phosphorylation and inactivation of the proapoptotic Bcl-2 family Protein BAD. IL-3 withdrawal-induced apoptosis is promoted by inhibition of JNK but suppressed by expression of a constitutively active JNK. JNK phosphorylates BAD at threonine 201, thereby inhibiting BAD association with the antiapoptotic molecule BCL-X L . IL-3 induces BAD phosphorylation at threonine 201, and replacement of threonine 201 by alanine generates a BAD mutant, which promotes IL-3 withdrawal-induced apoptosis. Thus, our results provide a molecular mechanism by which JNK contributes to cell survival.
Craig B Thompson - One of the best experts on this subject based on the ideXlab platform.
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Putting the Rap on Akt
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2004Co-Authors: James E. Thompson, Craig B ThompsonAbstract:The Protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic Protein BAD, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we d...
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the serine threonine kinase pim 2 is a transcriptionally regulated apoptotic inhibitor
Genes & Development, 2003Co-Authors: Peter S Hammerman, Ryan M Cinalli, Stephen R Master, Lewis A Chodosh, Craig B ThompsonAbstract:Growth factor withdrawal results in the termination of factor-dependent transcription. One transcript that declines rapidly following growth factor deprivation of hematopoietic cells is the serine/threonine kinase pim-2. When constitutively expressed, Pim-2 conferred long-term resistance to a variety of apoptotic stimuli including growth factor withdrawal and endogenous levels of Pim-2 contributed to growth factor-mediated apoptotic resistance. Pim-2 expression maintained cell size and mitochondrial potential independently of the PI3K/Akt/TOR pathway. Pim-2-dependent maintenance of cell size and survival correlated with its ability to maintain rapamycin-resistant phosphorylation of the translational repressor 4E-BP1 and phosphorylation of the BH3 Protein BAD. These results establish Pim-2 as a direct link between growth factor-induced transcription and a novel, kinase-dependent pathway that promotes cell-autonomous survival.
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The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitor
Genes & development, 2003Co-Authors: Casey J. Fox, Peter S Hammerman, Ryan M Cinalli, Stephen R Master, Lewis A Chodosh, Craig B ThompsonAbstract:Growth factor withdrawal results in the termination of factor-dependent transcription. One transcript that declines rapidly following growth factor deprivation of hematopoietic cells is the serine/threonine kinase pim-2. When constitutively expressed, Pim-2 conferred long-term resistance to a variety of apoptotic stimuli including growth factor withdrawal and endogenous levels of Pim-2 contributed to growth factor-mediated apoptotic resistance. Pim-2 expression maintained cell size and mitochondrial potential independently of the PI3K/Akt/TOR pathway. Pim-2-dependent maintenance of cell size and survival correlated with its ability to maintain rapamycin-resistant phosphorylation of the translational repressor 4E-BP1 and phosphorylation of the BH3 Protein BAD. These results establish Pim-2 as a direct link between growth factor-induced transcription and a novel, kinase-dependent pathway that promotes cell-autonomous survival.
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BAD, a heterodimeric partner for Bcl-xL and Bcl-2, displaces bax and promotes cell death
Cell, 1995Co-Authors: Elizabeth Yang, Craig B Thompson, Jiping Zha, Jennifer Jockel, Lawrence H. Boise, Stanley J. KorsmeyerAbstract:To extend the mammalian cell death pathway, we screened for further Bcl-2 interacting Proteins. Both yeast two-hybrid screening and lambda expression cloning identified a novel interacting Protein, BAD, whose homology to Bcl-2 is limited to the BH1 and BH2 domains. BAD selectively dimerized with Bcl-xL as well as Bcl-2, but not with Bax, Bcl-xs, Mcl-1, A1, or itself. BAD binds more strongly to Bcl-xL than Bcl-2 in mammalian cells, and it reversed the death repressor activity of Bcl-xL, but not that of Bcl-2. When BAD dimerized with Bcl-xL, Bax was displaced and apoptosis was restored. When approximately half of Bax was heterodimerized, death was inhibited. The susceptibility of a cell to a death signal is determined by these competing dimerizations in which levels of BAD influence the effectiveness of Bcl-2 versus Bcl-xL in repressing death.
