Transcription Factor CHOP

About: Transcription Factor CHOP is a research topic. Over the lifetime, 443 publications have been published within this topic receiving 46408 citations.

Endoplasmic Reticulum Stress in Pancreatic Neuroendocrine Tumors is Linked to Clinicopathological Parameters and Possible Epigenetic Regulations

Abstract: Background Endoplasmic reticulum (ER) stress is a highly-conserved cellular defense mechanism in response to perturbations of ER function. The role of ER stress in pancreatic neuroendocrine tumors (pNET) still remains unclear. Materials and methods We analyzed the protein expression pattern of the four key players of ER stress, (chaperone binding imunoglobluin protein (BiP), C/EBP homologous protein (CHOP), activating transcription factor 4 (ATF4) and caspase 4) as well as histone deacetylases (HDACs) by a tissue microarray (TMA) of 49 human pNET resected between 1997 and 2013 following, extensive clinicopathological characterization. Results Immunohistochemical profiling revealed a significant up-regulation of BiP, ATF4, CHOP and caspase 4 in pNET cases compared to normal controls. Correlated to clinicopathological parameters especially BiP expression could be linked to higher grading and proliferation as well as to lower survival probability. Finally, expression of ER stress markers correlated with HDAC expression in situ and pharmalogical inhibition by panobinostat significantly reduced cell viability in vitro. Conclusion Up-regulation of ER stress in pNET indicates the presence and engagement of ER stress signaling in this tumor entity demonstrating another possible anticancer therapy option in pNET.

Modulation of Pancreatic Islets' Function and Survival During Aging Involves the Differential Regulation of Endoplasmic Reticulum Stress by p21 and CHOP.

Abstract: Aims: Although endoplasmic reticulum (ER) stress is recognized as a major mechanism causing pancreatic dysfunction in diabetes, little is known on how aging modulates the process. Here, we compared the response with ER stress, viability, and insulin release from pancreatic islets of young (6 weeks) or aged (14 months) mice. Results: Islets from aged mice were more sensitive to ER stress than their younger counterparts; they exhibited more pronounced unfolded protein response (UPR) and caspase activation and displayed compromised insulin release after high-glucose stimulation. Genetic ablation of p21 sensitized the islets to ER stress, especially in the aged group, whereas CHOP ablation was protective for islets from both aged and younger animals. Ciclopirox (CPX), an iron chelator that stimulates p21 expression, protected islets from glucotoxicity and mice from diet-induced diabetes, especially in the aged group in a manner that was both p21 and CHOP dependent. Innovation: For the first time, the...

Is there a common upstream link for autophagic and apoptotic cell death in human high-grade gliomas?

Abstract: The prognosis of patients with human high-grade gliomas (HGGs) remains dismal despite major advances in their management, due mainly to the high resistance of these infiltrative tumor cells to programmed cell death (PCD). Most therapeutic strategies for HGGs are aimed to maximize PCD type I, apoptosis or type II, autophagy. These are predominantly distinctive processes, but many studies suggest a cross-talk between the two. A better understanding of the link between PCD types I and II might allow development of more effective therapies for HGGs. In this study, we examined whether there is a common upstream signaling event responsible for both apoptotic and autophagic PCD using 3 chemotherapeutic agents in human HGG cells. Our study shows that each agent caused a significant decrease in cell viability in each of the HGG cell lines tested. The increase rate of apoptosis and autophagy varied among cell lines and chemotherapeutic agents used. Increased expression of cytidine-cytidine-adenosine-adenosine-thymidine (C)/enhancer binding protein (EBP) homologous transcription factor C/EBP homologous protein (CHOP)/growth arrest and DNA damage–inducible gene 153 (GADD153) was documented after use of either pro-autophagic or pro-apoptotic agents. The involvement of CHOP/GADD153 in both type I and type II PCD was confirmed by overexpression and gene-silencing studies. Gene silencing by small-interfering RNA–mediated CHOP/GADD153 resulted in increased cell viability, decreased upregulation of microtubule-associated protein light-chain 3′ type II (LC3II) and cleaved caspase-3, and inhibition of apoptosis and autophagy. Exogenous expression of CHOP/GADD153 triggered apoptosis and autophagy in the absence of other stimuli. The clinical significance of these findings was supported by the evidence that celecoxib, a nonsteroidal anti-inflammatory drug known to induce GADD153-mediated apoptosis, strongly increases both type I and type II PCD in HGG cells when combined with another inducer of GADD153. These data suggest that CHOP/GADD153 should be investigated as a novel targetable signaling step to improve therapies for HGGs.

Involvement of endoplasmic reticulum stress-mediated CHOP (GADD153) induction in the cytotoxicity of 2-aminophenoxazine-3-one in cancer cells

Abstract: In this study, 2-aminophenoxazine-3-one (Phx-3) exhibited a potent cell growth inhibitory effect with apoptotic features in a dose-dependent manner in various cancer cell lines tested. Comparison of the expression profiles of endoplasmic reticulum (ER) stress-related genes in U266 multiple myeloma cells after treatment with Phx-3 and the ER stress inducers tunicamycin (TNM) and thapsigargin (TPG) indicated that although TNM and TPG potently induced pro-apoptotic transcription factor CHOP (GADD153) within 8 h of treatment, Phx-3 induced almost no CHOP within 48 h of treatment in U266 cells. However, murine embryonic fibroblast (MEF) cells and other cancer cell lines (e.g. A549 lung cancer cells and HL-60 acute leukemia cells) exhibited up-regulation of CHOP after treatment with Phx-3. The potency of CHOP induction in response to Phx-3 appeared to be partially correlated with the cytotoxic sensitivity of Phx-3 among various cell lines tested. MEF cells derived from CHOP knockout mice were more resistant to Phx-3 than wild-type MEF cells. Since Phx-3 has been shown to induce activation of NF-κB, a transcription factor functioning as a repressor of CHOP, we further treated U266 cells with a combination of Phx-3 and NF-κB inhibitors (e.g. BAY11-7082 or parthenolide). This enhanced cytotoxicity along with up-modulation of CHOP in U266 cells. These data suggest that ER stress-mediated CHOP induction by Phx-3 is involved in the cytotoxic effect. Regulation of CHOP expression appears to be a potent therapeutic target for cancer treatment.