Co-Treatment with Panobinostat Enhances Bortezomib-Induced Unfolded Protein Response, Endoplasmic Reticulum Stress and Apoptosis of Human Mantle Cell Lymphoma Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 887-887 ◽  
Author(s):  
Rekha Rao ◽  
Warren Fiskus ◽  
Yonghua Yang ◽  
Rajeshree Joshi ◽  
Pravina Fernandez ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Er Stress ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Mantle Cell ◽  
Protein Response

Abstract The 26S proteasome inhibitor bortezomib (BZ), which increases intracellular unfolded protein levels and toxicity through endoplasmic reticulum (ER) stress response, was shown to have a single agent activity in relapsed mantle cell lymphoma (MCL). Here we have determined that treatment with hydroxamic acid analogue (HA) pan-histone deacetylase (HDAC) inhibitor (HDI), e.g., panobinostat (LBH589, Novartis Pharmaceuticals Inc) induces the CDK inhibitors p21 and p27, and attenuates the levels of c-Myc, CDK4 and cyclin D1 in the cultured (Jeko-1, MO-2058 and Granta-519) and in primary patient-derived MCL cells. In a dose-dependent manner, panobinostat also induced Bax and Bak, and attenuated Bcl-xL, XIAP, survivin, AKT and c-Raf levels, resulting in growth inhibition and apoptosis of MCL cells. We have previously demonstrated that HDAC6 deacetylates heat shock protein (hsp) 90, as well as shuttles and sequesters misfolded and polyubiquitylated proteins into the protective perinuclear aggresome.. By inhibiting HDAC6, panobinostat (10 to 50 nM) induced acetylation of hsp90 in MCL cells. This inhibited the ATP binding and co-chaperone association, and abrogated the chaperone function of hsp90 for the MCL- relevant, hsp90 client proteins, e.g., cyclin D1, CDK4, c-Raf and AKT in the cultured and primary MCL cells. Panobinostat mediated inhibition of HDAC6 abrogated formation of the aggresome and augmented endoplasmic reticulum (ER)-based unfolded protein response (UPR). Treatment of MCL cells with BZ induced the formation of aggresome (as detected by confocal immuno-fluorescence microscopy and electron microscopy), as well as induced UPR and ER stress response. The latter was associated with BZ-mediated increased levels of GRP78, the spliced form of XBP1 (XBP1s) and p-eIF2α protein. As compared to the control siRNA treated cells, knockdown of GRP78 by siRNA markedly increased BZ-induced CHOP and Noxa levels and significantly augmented BZ-induced apoptosis of cultured MCL cells. Co-treatment of MCL cells with panobinostat abrogated BZ-induced aggresome formation, decreased the levels of ATF4, XBP1s and p-eIF2α, as well as increased the levels of CHOP, Noxa and GADD34. Ultrastructural analysis of Jeko-1 cells also revealed that co-treatment with panobinostat and BZ showed pronounced ER dilatation compared to panobinostat treatment alone, suggestive of enhanced ER stress. Higher and persistent CHOP and Noxa levels suggested a protracted ER-stress, associated with synergistic increase in apoptosis of MCL but not normal CD34+ bone marrow progenitor cells (p < 0.01). Conversely, knockdown of CHOP levels by siRNA significantly inhibited panobinostat and BZ-induced cell death of MCL cells. Results of ongoing in vivo studies of panobinostat and/or BZ in the NOD/SCID mouse xenograft model of Jeko-1 MCL cells will be presented. These findings strongly support further in vivo evaluation of the efficacy of the combination of panobinostat with BZ against human MCL. Additionally, the findings create the rationale to develop targeted knockdown of GRP78 as a novel strategy to augment lethal ER stress due to panobinostat and BZ and resulting activity against MCL cells.

Targeting Histone Deacetylases and Unfolded Protein Mediated Endoplasmic Reticulum (ER) Stress as a Strategy Against Human Mantle Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1378-1378
Author(s):  
Rekha Rao ◽  
Warren Fiskus ◽  
Rajeshree Joshi ◽  
Jianguang Chen ◽  
Pravina Fernandez ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Cyclin D1 ◽  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Mantle Cell

Abstract Poor clinical outcome of therapy of Mantle Cell Lymphoma (MCL) has generated the need to develop and test novel treatments for human MCL. Here we have determined that treatment with hydroxamic acid analogue (HA) pan-histone deacetylase (HDAC) inhibitor (HDI), e.g., LBH589 (Novartis Pharmaceuticals Inc) and vorinostat (Merck Pharmaceuticals), induces the CDK inhibitors p21 and p27, and attenuates the levels of c-Myc, CDK4 and cyclin D1 in the cultured (Jeko-1, MO-2058 and Granta-519) and in primary patient-derived MCL cells. In a dose-dependent manner, HA-HDI also induced Bax, Bak and Bim, and attenuated Bcl-xL, XIAP, survivin, AKT and c-Raf levels, resulting in growth inhibition and apoptosis of MCL cells. We have previously demonstrated that HDAC6 deacetylates heat shock protein (hsp) 90. By inhibiting HDAC6, both LBH589 (10 to 50 nM) and vorinostat (0.5 to 2.0 uM) induced acetylation of hsp90 in MCL cells. This inhibited the ATP binding and co-chaperone association, and abrogated the chaperone function of hsp90 for the MCL- relevant, hsp90 client proteins, e.g., cyclin D1, CDK4, c-Raf and AKT in the cultured and primary MCL cells. HDAC6 has been shown to shuttle and sequester misfolded and polyubiquitylated proteins into the protective perinuclear aggresome. Present studies demonstrate that inhibition of HDAC6 abrogates formation of the aggresome and augments the ER-based unfolded protein response (UPR). Treatment of MCL cells with the proteasome inhibitor bortezomib (BZ) induced the formation of aggresome (as detected by confocal immuno-fluorescence microscopy and electron microscopy), as well as induced UPR and ER stress response. The latter was associated with BZ-mediated increased levels of the spliced form of XBP1 (XBP1s) and p-eIF2α protein. It was also associated with increased levels of the protective ER chaperone protein GRP78, and increased expression of pro-death proteins, CHOP and Noxa. Treatment with BZ or HA-HDI also increased the expression of the transcriptional repressor, PRDM1. Co-treatment of MCL cells with LBH589 abrogated BZ-induced aggresome formation, but increased the levels of BZ-induced XBP1s and p-eIF2α, indicating increased ER stress response. Concomitantly, higher CHOP and Noxa levels suggested a protracted ER-stress, associated with significantly increased apoptosis of MCL cells (p < 0.01). These findings suggest that co-treatment with LBH589 accentuates BZ-induced ER-stress and cell death of MCL cells despite up-regulation of GRP78 levels. Next, we determined the effects of knocking down GRP78 on BZ-induced ER-stress response. As compared to the control siRNA treated cells, knockdown by siRNA to GRP78 markedly increased BZ-induced CHOP and Noxa levels and significantly augmented BZ-induced apoptosis of cultured MCL cells. Collectively, these findings strongly support the in vivo testing of the efficacy of the combination of HA-HDI with BZ in inducing protracted and lethal ER stress in MCL cells. These results also create the rationale to develop targeted knockdown of GRP78 as a novel strategy to augment the lethal ER stress in human MCL cells.

Bortezomib Induces an Antioxidant and ER-Stress Response Gene Expression Signature in Mantle Cell Lymphoma: Implications for Response Prediction and Optimized Chemotherapy Regimens.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 830-830
Author(s):  
Edgar G. Rizzatti ◽  
Helena Mora-Jensen ◽  
Raymond Lai ◽  
Masanori Daibata ◽  
Therese White ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stress Response ◽  
Er Stress ◽  
Mantle Cell Lymphoma ◽  
Cell Lines ◽  
Cell Lymphoma ◽  
Er Stress Response ◽  
Mantle Cell ◽  
Sensitive Group ◽  
Resistant Cells

Abstract Mantle cell lymphoma (MCL) is an aggressive and incurable B-cell lymphoma for which new treatment options are needed. Recent phase II clinical trials reported response to the proteasome inhibitor bortezomib (BZM) in up to 50% of pre-treated patients. Despite the successful use of BZM in the clinic, the precise molecular mechanisms underlying sensitivity or resistance to BZM in MCL remain largely unknown. To address this issue, we used U133A 2.0 microarrays to analyze gene expression in MCL cells from peripheral blood of 5 patients with previously untreated leukemic MCL. Samples were collected immediately before (0h) and at 3, 6, 24, and 72 hours after administration of BZM (1.5 mg/m2). After the blood collection at 72 hours, a second dose of BZM was given, and cells were collected 24 hours later. Two patients had major reductions in peripheral ALC already at 24h from dose 2 and normalized their blood counts by day 21 (sensitive), 1 patient had no change over a full course of 4 injections (resistant), and 2 patients had some decrease in ALC (intermediate). Genes differentially expressed with treatment were ranked according to the degree of correlation with time (Pearson). We used gene set enrichment analysis (GSEA) to detect distinct functional gene expression signatures; the most consistently up-regulated of which was a signature composed by proteasome and chaperone genes. To confirm and expand these findings, we exposed 10 MCL cell lines (7 sensitive, IC50&lt;10nM; 3 resistant IC50&gt;10nM) to 10nM of BZM and analyzed gene expression at 1, 3, 6 and 24 hours. The proteasome signature was again dominant, and the majority of the up-regulated genes in both clinical and cell line samples shared binding motifs for the NRF, MAF, ATF and HSF families of transcription factors (TF). Thus genes up-regulated by BZM in vivo and in cell lines predominantly belonged to a functional response to oxidative and/or endoplasmic reticulum (ER) stress. Under physiologic conditions, this is thought to help restore homeostasis and protect from apoptosis. This response could therefore contribute to drug resistance or be a marker of an overwhelming insult before the cells undergo apoptosis. To address this issue, we investigated differences in response to BZM between sensitive and resistant cell lines. The proteasome signature was more strongly up-regulated in sensitive cells than in resistant cells, and the ER-stress response as measured by genes controlled by the NRF and MAF family of TFs was also more highly expressed in the sensitive group. Consistently, expression of HMOX1, which encodes a key enzyme in the antioxidant response, was increased by 32× at 24h in the sensitive group, but only by 4× in the resistant group; the expression of DDIT3, a transcription factor implicated in a pro-apoptotic response to ER-stress was 5.5-fold up-regulated in the sensitive cells but only 1.4-fold in the resistant cells. We conclude that in sensitive cells BZM induces an overwhelming ER-stress response with high expression of proteasome components and chaperone proteins that could serve as a predictor of response to BZM.

scholarly journals The Drosophila metallopeptidase superdeath decouples apoptosis from the activation of the ER stress response

2019 ◽  
Author(s):  
Rebecca A.S. Palu ◽  
Clement Y. Chow
Keyword(s):  
Endoplasmic Reticulum ◽  
Drosophila Melanogaster ◽  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Membrane Bound ◽  
Induced Apoptosis ◽  
The Unfolded Protein Response ◽  
Protein Response

ABSTRACTEndoplasmic reticulum (ER) stress-induced apoptosis is a primary cause and modifier of degeneration in a number of genetic disorders. Understanding how genetic variation between individuals influences the ER stress response and subsequent activation of apoptosis could improve individualized therapies and predictions of outcomes for patients. In this study, we find that the uncharacterized, membrane-bound metallopeptidase CG14516 in Drosophila melanogaster, which we rename as SUPpressor of ER stress-induced DEATH (superdeath), plays a role in modifying ER stress-induced apoptosis. We demonstrate that loss of superdeath reduces apoptosis and degeneration in the Rh1G69D model of ER stress through the JNK signaling cascade. This effect on apoptosis occurs without altering the activation of the unfolded protein response (IRE1 and PERK), suggesting that the beneficial pro-survival effects of this response are intact. Furthermore, we show that superdeath functions epistatically upstream of CDK5, a known JNK-activated pro-apoptotic factor in this model of ER stress. We demonstrate that superdeath is not only a modifier of this particular model, but functions as a general modifier of ER stress-induced apoptosis across different tissues and ER stresses. Finally, we present evidence of Superdeath localization to the endoplasmic reticulum membrane. While similar in sequence to a number of human metallopeptidases found in the plasma membrane and ER membrane, its localization suggests that superdeath is orthologous to ERAP1/2 in humans. Together, this study provides evidence that superdeath is a link between stress in the ER and activation of cytosolic apoptotic pathways.SIGNIFICANCE STATEMENTGenetic diseases display a great deal of variability in presentation, progression, and overall outcomes. Much of this variability is caused by differences in genetic background among patients. One process that commonly modifies degenerative disease is the endoplasmic reticulum (ER) stress response. Understanding the genetic sources of variation in the ER stress response could improve individual diagnosis and treatment decisions. In this study, we characterized one such modifier in Drosophila melanogaster, the membrane-bound metallopeptidase CG14516 (superdeath). Loss of this enzyme suppresses a model of ER stress-induced degeneration by reducing cell death without altering the beneficial activation of the unfolded protein response. Our findings make superdeath and its orthologues attractive therapeutic targets in degenerative disease.

scholarly journals The aftermath of the interplay between the endoplasmic reticulum stress response and redox signaling

2021 ◽  
Author(s):  
Kashi Raj Bhattarai ◽  
Thoufiqul Alam Riaz ◽  
Hyung-Ryong Kim ◽  
Han-Jung Chae
Keyword(s):  
Endoplasmic Reticulum ◽  
Protein Folding ◽  
Stress Response ◽  
Er Stress ◽  
Protein Modification ◽  
Endoplasmic Reticulum Stress Response ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe endoplasmic reticulum (ER) is an essential organelle of eukaryotic cells. Its main functions include protein synthesis, proper protein folding, protein modification, and the transportation of synthesized proteins. Any perturbations in ER function, such as increased demand for protein folding or the accumulation of unfolded or misfolded proteins in the ER lumen, lead to a stress response called the unfolded protein response (UPR). The primary aim of the UPR is to restore cellular homeostasis; however, it triggers apoptotic signaling during prolonged stress. The core mechanisms of the ER stress response, the failure to respond to cellular stress, and the final fate of the cell are not yet clear. Here, we discuss cellular fate during ER stress, cross talk between the ER and mitochondria and its significance, and conditions that can trigger ER stress response failure. We also describe how the redox environment affects the ER stress response, and vice versa, and the aftermath of the ER stress response, integrating a discussion on redox imbalance-induced ER stress response failure progressing to cell death and dynamic pathophysiological changes.

Necroptosis activates UPR sensors without disrupting their binding with GRP78

2021 ◽  
Vol 118 (39) ◽  
pp. e2110476118
Author(s):  
Wei Liang ◽  
Weiwei Qi ◽  
Yang Geng ◽  
Linhan Wang ◽  
Jing Zhao ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Messenger Rna ◽  
Proximity Ligation Assay ◽  
Dependent Manner ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Regulated Necrosis ◽  
Protein Response

Necroptosis is a form of regulated necrosis mediated by the formation of the necrosome, composed of the RIPK1/RIPK3/MLKL complex. Here, we developed a proximity ligation assay (PLA) that allows in situ visualization of necrosomes in necroptotic cells and in vivo. Using PLA assay, we show that necrosomes can be found in close proximity to the endoplasmic reticulum (ER). Furthermore, we show that necroptosis activates ER stress sensors, PERK, IRE1α, and ATF6 in a RIPK1-RIPK3-MLKL axis–dependent manner. Activated MLKL can be translocated to the ER membrane to directly initiate the activation of ER stress signaling. The activation of IRE1α in necroptosis promotes the splicing of XBP1, and the subsequent incorporation of spliced XBP1 messenger RNA (mRNA) into extracellular vesicles (EVs). Finally, we show that unlike that of a conventional ER stress response, necroptosis promotes the activation of unfolded protein response (UPR) sensors without affecting their binding of GRP78. Our study reveals a signaling pathway that links MLKL activation in necroptosis to an unconventional ER stress response.

scholarly journals Endoplasmic Reticulum Stress-Induced Formation of Transcription Factor Complex ERSF Including NF-Y (CBF) and Activating Transcription Factors 6α and 6β That Activates the Mammalian Unfolded Protein Response

2001 ◽  
Vol 21 (4) ◽  
pp. 1239-1248 ◽  
Author(s):  
Hiderou Yoshida ◽  
Tetsuya Okada ◽  
Kyosuke Haze ◽  
Hideki Yanagi ◽  
Takashi Yura ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Transcription Factors ◽  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Consensus Sequence ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
Protein Response ◽  
Transcriptional Induction

ABSTRACT The levels of molecular chaperones and folding enzymes in the endoplasmic reticulum (ER) are controlled by a transcriptional induction process termed the unfolded protein response (UPR). The mammalian UPR is mediated by the cis-acting ER stress response element (ERSE), the consensus sequence of which is CCAAT-N9-CCACG. We recently proposed that ER stress response factor (ERSF) binding to ERSE is a heterologous protein complex consisting of the constitutive component NF-Y (CBF) binding to CCAAT and an inducible component binding to CCACG and identified the basic leucine zipper-type transcription factors ATF6α and ATF6β as inducible components of ERSF. ATF6α and ATF6β produced by ER stress-induced proteolysis bind to CCACG only when CCAAT is bound to NF-Y, a heterotrimer consisting of NF-YA, NF-YB, and NF-YC. Interestingly, the NF-Y and ATF6 binding sites must be separated by a spacer of 9 bp. We describe here the basis for this strict requirement by demonstrating that both ATF6α and ATF6β physically interact with NF-Y trimer via direct binding to the NF-YC subunit. ATF6α and ATF6β bind to the ERSE as a homo- or heterodimer. Furthermore, we showed that ERSF including NF-Y and ATF6α and/or β and capable of binding to ERSE is indeed formed when the cellular UPR is activated. We concluded that ATF6 homo- or heterodimers recognize and bind directly to both the DNA and adjacent protein NF-Y and that this complex formation process is essential for transcriptional induction of ER chaperones.

scholarly journals NOD1/NOD2 and RIP2 Regulate Endoplasmic Reticulum Stress-Induced Inflammation during Chlamydia Infection

mBio ◽  
2020 ◽  
Vol 11 (3) ◽  
Author(s):  
Oanh H. Pham ◽  
Bokyung Lee ◽  
Jasmine Labuda ◽  
A. Marijke Keestra-Gounder ◽  
Mariana X. Byndloss ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Stress Response ◽  
Inflammatory Response ◽  
Endoplasmic Reticulum Stress ◽  
Er Stress ◽  
Young Women ◽  
The United States ◽  
Chlamydia Infection ◽  
Er Stress Response

ABSTRACT The inflammatory response to Chlamydia infection is likely to be multifactorial and involve a variety of ligand-dependent and -independent recognition pathways. We previously reported the presence of NOD1/NOD2-dependent endoplasmic reticulum (ER) stress-induced inflammation during Chlamydia muridarum infection in vitro, but the relevance of this finding to an in vivo context is unclear. Here, we examined the ER stress response to in vivo Chlamydia infection. The induction of interleukin 6 (IL-6) production after systemic Chlamydia infection correlated with expression of ER stress response genes. Furthermore, when tauroursodeoxycholate (TUDCA) was used to inhibit the ER stress response, an increased bacterial burden was detected, suggesting that ER stress-driven inflammation can contribute to systemic bacterial clearance. Mice lacking both NOD1 and NOD2 or RIP2 exhibited slightly higher systemic bacterial burdens after infection with Chlamydia. Overall, these data suggest a model where RIP2 and NOD1/NOD2 proteins link ER stress responses with the induction of Chlamydia-specific inflammatory responses. IMPORTANCE Understanding the initiation of the inflammatory response during Chlamydia infection is of public health importance given the impact of this disease on young women in the United States. Many young women are chronically infected with Chlamydia but are asymptomatic and therefore do not seek treatment, leaving them at risk of long-term reproductive harm due to inflammation in response to infection. Our manuscript explores the role of the endoplasmic reticulum stress response pathway initiated by an innate receptor in the development of this inflammation.

Treatment with Histone Deacetylase 6-Specific Inhibitor WT-161 Disrupts hsp90 Function, Abrogates Aggresome Formation and Sensitizes Human Mantle Cell Lymphoma Cells to Lethal ER Stress Induced by Proteasome Inhibitor Carfilzomib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2856-2856 ◽  
Author(s):  
Rekha Rao ◽  
Warren Fiskus ◽  
Ramesh Balusu ◽  
Hongwei Ma ◽  
James Bradner ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Histone Deacetylase ◽  
Proteasome Inhibitor ◽  
Cell Lymphoma ◽  
Specific Inhibitor ◽  
Er Stress Response ◽  
Mantle Cell ◽  
Aggresome Formation ◽  
Induced Apoptosis

Abstract Abstract 2856 The proteasome inhibitor bortezpmib has been shown to markedly increase the intracellular levels of misfolded proteins, induce aggresome formation and cause endoplasmic reticulum (ER) stress, resulting in apoptosis of human Mantle Cell Lymphoma (MCL) cells. Consistent with this, Bortezomib displays clinical efficacy in patients with relapsed and refractory MCL. We have recently reported that the pan-histone deacetylase (HDAC) inhibitor panobinostat, by also inhibiting HDAC6, abrogates aggresome formation and induces Endoplasmic Stress (ER) stress, as well as potentiates bortezomib-induced apoptosis of MCL cells. Here, we determined the anti-MCL cell activity of an HDAC6-specific inhibitor, WT-161 alone and in combination with the novel, orally bio-available, proteasome inhibitor carfilzomib (Proteolix Inc.) against human, cultured and primary, patient-derived MCL cells. Treatment with WT-161 (0.1 to 1.0 uM) resulted in a dose-dependent increase in the acetylation of alpha-tubulin and heat shock protein (hsp) 90, without any appreciable increase in the levels of acetylated histone (H) 3. Consistent with WT-161 mediated hyperacetylation and inhibition of hsp90 chaperone function, treatment with WT-161 increased the intracellular levels of polyubiuitylated proteins in the cultured MCL JeKo-1 and Z138 cells. WT-161 was also noted to dose-dependently deplete the levels of cyclin D1 in the cultured MCL cells. Treatment with WT-161 also induced ER stress response in the MCL cells, demonstrated by increase in the protein levels of Glucose regulated protein (GRP) 78, phosphorylated eIF2 (eukaryotic initation factor 2) α, and induction of the pro-apoptotic transcription factor CHOP (CAAT/Enhancer Binding Protein Homologous Protein). We next determined the effects of co-treatment with WT-161 on carfilzomib-induced aggresome formation, ER stress response and apoptosis of the cultured and primary MCL cells. Co-treatment with WT-161 (0.25 uM) abrogated carfilzomib-induced aggresome formation in MCL cells, as evidenced by confocal immunofluorescent staining of aggresomes with anti-HDAC6 and anti-ubiquitin antibodies. Compared to each agent alone, co-treatment with WT-161 and carfilzomib induced more intracellular polyubiquitylated proteins and induced higher levels of CHOP in the cultured MCL cells. Co-treatment with WT-161 and carfilzomib also synergistically induced apoptosis of the cultured MCL cells (combination indices < 1.0). Notably, co-treatment with WT-161 and carfilzomib also synergistically induced apoptosis of primary MCL cells (combination indices < 1.0). These findings strongly support the in vivo testing of the combination of an HDAC6-specific inhibitor such as WT-161 with the proteasome inhibitor carfilzomib against human MCL cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals HY5, a positive regulator of light signaling, negatively controls the unfolded protein response inArabidopsis

2017 ◽  
Vol 114 (8) ◽  
pp. 2084-2089 ◽  
Author(s):  
Ganesh M. Nawkar ◽  
Chang Ho Kang ◽  
Punyakishore Maibam ◽  
Joung Hun Park ◽  
Young Jun Jung ◽  
...  
Keyword(s):  
Stress Response ◽  
Er Stress ◽  
Unfolded Protein Response ◽  
Molecular Mechanism ◽  
26S Proteasome ◽  
Light Signaling ◽  
Unfolded Protein ◽  
Er Stress Response ◽  
The Unfolded Protein Response ◽  
Protein Response

Light influences essentially all aspects of plant growth and development. Integration of light signaling with different stress response results in improvement of plant survival rates in ever changing environmental conditions. Diverse environmental stresses affect the protein-folding capacity of the endoplasmic reticulum (ER), thus evoking ER stress in plants. Consequently, the unfolded protein response (UPR), in which a set of molecular chaperones is expressed, is initiated in the ER to alleviate this stress. Although its underlying molecular mechanism remains unknown, light is believed to be required for the ER stress response. In this study, we demonstrate that increasing light intensity elevates the ER stress sensitivity of plants. Moreover, mutation of the ELONGATED HYPOCOTYL 5 (HY5), a key component of light signaling, leads to tolerance to ER stress. This enhanced tolerance ofhy5plants can be attributed to higher expression of UPR genes. HY5 negatively regulates the UPR by competing with basic leucine zipper 28 (bZIP28) to bind to the G-box–like element present in the ER stress response element (ERSE). Furthermore, we found that HY5 undergoes 26S proteasome-mediated degradation under ER stress conditions. Conclusively, we propose a molecular mechanism of crosstalk between the UPR and light signaling, mediated by HY5, which positively mediates light signaling, but negatively regulates UPR gene expression.

scholarly journals A Novel Transcription Factor, ERD15 (Early Responsive to Dehydration 15), Connects Endoplasmic Reticulum Stress with an Osmotic Stress-induced Cell Death Signal

2011 ◽  
Vol 286 (22) ◽  
pp. 20020-20030 ◽  
Author(s):  
Murilo S. Alves ◽  
Pedro A. B. Reis ◽  
Silvana P. Dadalto ◽  
Jerusa A. Q. A. Faria ◽  
Elizabeth P. B. Fontes ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Cell Death ◽  
Transcription Factor ◽  
Osmotic Stress ◽  
Er Stress ◽  
Unfolded Protein ◽  
Eukaryotic Organisms ◽  
Protein Response

As in all other eukaryotic organisms, endoplasmic reticulum (ER) stress triggers the evolutionarily conserved unfolded protein response in soybean, but it also communicates with other adaptive signaling responses, such as osmotic stress-induced and ER stress-induced programmed cell death. These two signaling pathways converge at the level of gene transcription to activate an integrated cascade that is mediated by N-rich proteins (NRPs). Here, we describe a novel transcription factor, GmERD15 (Glycine max Early Responsive to Dehydration 15), which is induced by ER stress and osmotic stress to activate the expression of NRP genes. GmERD15 was isolated because of its capacity to stably associate with the NRP-B promoter in yeast. It specifically binds to a 187-bp fragment of the NRP-B promoter in vitro and activates the transcription of a reporter gene in yeast. Furthermore, GmERD15 was found in both the cytoplasm and the nucleus, and a ChIP assay revealed that it binds to the NRP-B promoter in vivo. Expression of GmERD15 in soybean protoplasts activated the NRP-B promoter and induced expression of the NRP-B gene. Collectively, these results support the interpretation that GmERD15 functions as an upstream component of stress-induced NRP-B-mediated signaling to connect stress in the ER to an osmotic stress-induced cell death signal.

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