Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity

Low, Ivan Cherh Chiet; Loh, Thomas Kwok Seng; Huang, Yiqing; Virshup, David M.; Pervaiz, Shazib

doi:10.1182/blood-2014-03-563296

Cited by 77 publications

(67 citation statements)

References 37 publications

(37 reference statements)

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“…In animals, PP2A is a well-known tumor suppressor. ROS accumulation in cancer cells causes nitration and inactivation of PP2A, which interferes with the interaction of Bcl-2 with the PP2A catalytic core, leading to increased phosphorylation and antiapoptotic activity of Bcl-2 [38]. We recently reported that V .…”

Section: Discussionmentioning

confidence: 99%

Secretory proteins are delivered to the septin-organized penetration interface during root infection by Verticillium dahliae

2017

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Successful infection of the host requires secretion of effector proteins to evade or suppress plant immunity. Secretion of effectors in root-infecting fungal pathogens, however, remains unexplored. We previously reported that Verticillium dahliae, a root-infecting phytopathogenic fungus, develops a penetration peg from a hyphopodium to infect cotton roots. In this study, we report that a septin ring, requiring VdSep5, partitions the hyphopodium and the invasive hypha and form the specialized fungus-host interface. The mutant strain, VdΔnoxb, in which NADPH oxidase B (VdNoxB) is deleted, impaired formation of the septin ring at the hyphal neck, indicating that NADPH oxidases regulate septin ring organization. Using GFP tagging and live cell imaging, we observed that several signal peptide containing secreted proteins showed ring signal accumulation/secretion at the penetration interface surrounding the hyphal neck. Targeted mutation for VdSep5 reduced the delivery rate of secretory proteins to the penetration interface. Blocking the secretory pathway by disrupting the vesicular trafficking factors, VdSec22 and VdSyn8, or the exocyst subunit, VdExo70, also arrested delivery of the secreted proteins inside the hyphopodium. Reduced virulence was observed when cotton roots were infected with VdΔsep5, VdΔsec22, VdΔsyn8 and VdΔexo70 mutants compared to infection with the isogenic wild-type V592. Taken together, our data demonstrate that the hyphal neck is an important site for protein secretion during plant root infection, and that the multiple secretory routes are involved in the secretion.

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Section: Discussionmentioning

confidence: 99%

Secretory proteins are delivered to the septin-organized penetration interface during root infection by Verticillium dahliae

2017

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“…We co-localized LMO4 and nitrotyrosine in the outer hair cells, which are primary targets of cisplatin-induced ototoxicity [4]. Protein nitration can modulate phosphorylation cascades, alter protein function, and facilitate proteolytic degradation of nitrated proteins [28], [29], [30], [31], [32], [33], [34]. Consistent with these reports, cisplatin-induced nitration of LMO4 was associated with a significant decrease in its protein levels, not only in the auditory cells, but in the renal and neuronal cells, which are also susceptible to the toxic side-effects of cisplatin [35].…”

Section: Introductionmentioning

confidence: 99%

Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity

2016

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Cisplatin-induced ototoxicity remains a primary dose-limiting adverse effect of this highly effective anticancer drug. The clinical utility of cisplatin could be enhanced if the signaling pathways that regulate the toxic side-effects are delineated. In previous studies, we reported cisplatin-induced nitration of cochlear proteins and provided the first evidence for nitration and downregulation of cochlear LIM domain only 4 (LMO4) in cisplatin ototoxicity. Here, we extend these findings to define the critical role of nitrative stress in cisplatin-induced downregulation of LMO4 and its consequent ototoxic effects in UBOC1 cell cultures derived from sensory epithelial cells of the inner ear and in CBA/J mice. Cisplatin treatment increased the levels of nitrotyrosine and active caspase 3 in UBOC1 cells, which was detected by immunocytochemical and flow cytometry analysis, respectively. The cisplatin-induced nitrative stress and apoptosis were attenuated by co-treatment with SRI110, a peroxynitrite decomposition catalyst (PNDC), which also attenuated the cisplatin-induced downregulation of LMO4 in a dose-dependent manner. Furthermore, transient overexpression of LMO4 in UBOC1 cells prevented cisplatin-induced cytotoxicity while repression of LMO4 exacerbated cisplatin-induced cell death, indicating a direct link between LMO4 protein levels and cisplatin ototoxicity. Finally, auditory brainstem responses (ABR) recorded from CBA/J mice indicated that co-treatment with SRI110 mitigated cisplatin-induced hearing loss. Together, these results suggest that cisplatin-induced nitrative stress leads to a decrease in the levels of LMO4, downregulation of LMO4 is a critical determinant in cisplatin-induced ototoxicity, and targeting peroxynitrite could be a promising strategy for mitigating cisplatin-induced hearing loss.

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“…It could directly disrupt the Bcl‐2/Bax association to liberate Bax from the heterodimer complex . In Drosophila, knock down or loss of either of the subunits A, C, or B56 leads to hyper phosphorylation of Bcl‐2, thus initiating p53‐mediated apoptosis . The purpose of this study was to evaluate JS‐K as a cutative agent for HCC.…”

Section: Discussionmentioning

confidence: 99%

Protein phosphatase 2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family proteins in human hepatocellular carcinoma HepG2 cells

Liu

Huang

Chen

et al. 2018

J of Cellular Biochemistry

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Protein phosphatase 2A (PP2A) is an important enzyme within various signal transduction pathways. The present study was investigated PP2A mediates JS-K-induced apoptosis by affecting Bcl-2 family protein. JS-K showed diverse inhibitory effects in five HCC cell lines, especially HepG2 cells. JS-K caused a dose- and time-dependent reduction in cell viability and increased in levels of LDH release. Meanwhile, JS-K- induced apoptosis was characterized by mitochondrial membrane potential reduction, Hoechst 33342 /PI dual staining, release of cytochrome c (Cyt c), and activation of cleaved caspase-9/3. Moreover, JS-K-treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C), decrease of anti-apoptotic Bcl-2 family-protein expression including p-Bcl-2 (Ser70), Bcl-2, Bcl-xL, and Mcl-1 as well as the increase of pro-apoptosis Bcl-2 family-protein including Bim, Bad, Bax, and Bak. Furthermore, JS-K caused a marked increase of intracellular NO levels while pre-treatment with Carboxy-PTIO (a NO scavenger) reduced the cytotoxicity effects and the apoptosis rate. Meanwhile, pre-treatment with Carboxy-PTIO attenuated the JS-K-induced up-regulation of PP2A, Cyt c, and cleaved-caspase-9/3 activation. The silencing PP2A-C by siRNA could abolish the activation of PP2A-C, down-regulation of anti-apoptotic Bcl-2 family-protein (p-Bcl-2, Bcl-2, Bcl-xL, and Mcl-1), increase of pro-apoptosis Bcl-2 family-protein (Bim, Bad, Bax, and Bak) and apoptotic-related protein (Cyt c, cleaved caspase-9/3) that were caused by JS-K in HepG2 cells. In addition, pre-treatment with OA (a PP2A inhibitor) also attenuated the above effects induced by JS-K. In summary, NO release from JS-K induces apoptosis through PP2A activation, which contributed to the regulation of Bcl-2 family proteins.

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Ser70 phosphorylation of Bcl-2 by selective tyrosine nitration of PP2A-B56δ stabilizes its antiapoptotic activity

Abstract: Key Points O2− modifies B56δ at Y289 to block the PP2A holoenzyme assembly. This results in S70 Bcl-2 phosphorylation and promotes tumor chemoresistance. Primary lymphomas with low SOD1 have high B56δ tyrosine nitration and S70pBcl-2.

Cited by 77 publications

References 37 publications

Secretory proteins are delivered to the septin-organized penetration interface during root infection by Verticillium dahliae

Secretory proteins are delivered to the septin-organized penetration interface during root infection by Verticillium dahliae

Targeting nitrative stress for attenuating cisplatin-induced downregulation of cochlear LIM domain only 4 and ototoxicity

Protein phosphatase 2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family proteins in human hepatocellular carcinoma HepG2 cells

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