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.

Valproate attenuates diabetic nephropathy through inhibition of endoplasmic reticulum stress‑induced apoptosis

Abstract: Previous studies have suggested that endoplasmic reticulum stress (ERS) is one of the mechanisms responsible for the pathogenesis of diabetic nephropathy (DN). Histone acetylation modification can regulate the transcription of genes and is involved in the regulation of ERS. Valproate (VPA), a nonselective histone deacetylase inhibitor, has been reported to have a protective role in kidney tissue injury, however, whether VPA can prevent DN remains to be elucidated. In the present study, it was found that VPA increases the expression of glucose‑regulated protein (GRP78) and reduces the protein expression of C/EBP‑homologous protein (CHOP), growth arrest and DNA‑damage‑inducible gene 153 and caspase‑12 in a rat model of DN. VPA can reduce renal cell apoptosis and alleviate proteinuria and alterations in serum creatinine. VPA also upregulates the acetylation level of histone H4 in the promoter of GRP78 and downregulates the acetylation level of histone H4 in the promoter of CHOP. Collectively, the data indicate that VPA can relieve ERS and reduce renal cell apoptosis, and thus attenuate renal injury in a rat model of DN by regulating the acetylation level of histone H4 in ERS‑associated protein promoters.

HIV-1 gp120 induces type-1 programmed cell death through ER stress employing IRE1α, JNK and AP-1 pathway

Abstract: The ER stress-mediated apoptosis has been implicated in several neurodegenerative diseases; however, its role in HIV/neuroAIDS remains largely unexplored. The present study was undertaken to assess the involvement and detailed mechanism of IRE1α pathway in HIV-1 gp120-mediated ER stress and its possible involvement in cell death. Various signaling molecules for IRE1α pathway were assessed using SVGA cells, primary astrocytes and gp120 transgenic mice, which demonstrated gp120-mediated increase in phosphorylated JNK, XBP-1 and AP-1 leading to upregulation of CHOP. Furthermore, HIV-1 gp120-mediated activation of IRE1α also increased XBP-1 splicing. The functional consequence of gp120-mediated ER stress was determined via assessment of gp120-mediated cell death using PI staining and MTT assay. The gp120-mediated cell death also involved caspase-9/caspase-3-mediated apoptosis. These findings were confirmed with the help of specific siRNA for IRE1α, JNK, AP-1, BiP and CHOP showing significant reduction in gp120-mediated CHOP expression. Additionally, silencing all the intermediates also reduced the gp120-mediated cell death and caspase-9/caspase-3 activation at differential levels. This study provides ER-stress as a novel therapeutic target in the management of gp120-mediated cell death and possibly in the treatment of neuroAIDS.

Resveratrol-induced cytotoxicity in human Burkitt's lymphoma cells is coupled to the unfolded protein response.

Abstract: Resveratrol (RES), a natural phytoalexin found at high levels in grapes and red wine, has been shown to induce anti-proliferation and apoptosis of human cancer cell lines. However, the underlying molecular mechanisms are at present only partially understood. The effects of RES on activation of unfolded protein responses (UPR) were evaluated using Western blotting, semi-quantitative and real-time RT-PCR. Cell death was evaluated using Annexin V/PI staining and subsequent FACS. Similar as tunicamycin, treatment with RES lead to the activation of all 3 branches of the UPR, with early splicing of XBP-1 indicative of IRE1 activation, phosphorylation of eIF2α consistent with ER resident kinase (PERK) activation, activating transcription factor 6 (ATF6) splicing, and increase in expression levels of the downstream molecules GRP78/BiP, GRP94 and CHOP/GADD153 in human Burkitt's lymphoma Raji and Daudi cell lines. RES was shown to induce cell death, which could be attenuated by thwarting upregulation of CHOP. Our data suggest that activation of the apoptotic arm of the UPR and its downstream effector CHOP/GADD153 is involved, at least in part, in RES-induced apoptosis in Burkitt's lymphoma cells.

Role of C/EBP homologous protein in retinal ganglion cell death after ischemia/reperfusion injury.

Abstract: PURPOSE To investigate the role of C/EBP homologous protein (CHOP), a proapoptotic protein, and the unfolded protein response (UPR) marker that is involved in endoplasmic reticulum (ER) stress-mediated apoptosis in mouse retinal ganglion cell (RGC) death following ischemia/reperfusion (I/R) injury. METHODS Retinal I/R injury was induced in adult C57BL/6J wild-type (WT) and CHOP knockout (Chop(-/-)) mice by raising IOP to 120 mm Hg for 60 minutes. Expression of CHOP and other UPR markers was studied by Western blot and immunohistochemistry. Retinal ganglion cell counts were performed in retinal flat mounts stained with an RGC marker. Retinal ganglion cell function was evaluated by scotopic threshold response (STR) electroretinography. RESULTS In WT mice, retinal CHOP was upregulated by 30% in I/R-injured eyes compared to uninjured eyes 3 days after injury (P < 0.05). Immunohistochemistry confirmed CHOP upregulation specifically in RGCs. CHOP knockout did not affect baseline RGC density or STR amplitude. Ischemia/reperfusion injury decreased RGC densities and STR amplitudes in both WT and Chop(-/-) mice. However, survival of RGCs in I/R-injured Chop(-/-) mouse was 48% higher (P < 0.05) than that in I/R-injured WT mouse 3 days after I/R injury. Similarly, RGC density was significantly higher in Chop(-/-) eyes at 7, 14, and 28 days after I/R injury. Scotopic threshold response amplitudes of Chop(-/-) mice were significantly higher at 3 and 7 days after I/R than those of WT mice. CONCLUSIONS Absence of CHOP partially protects against RGC loss and reduction in retinal function after I/R injury, indicating that CHOP and, thus, ER stress play an important role in RGC apoptosis in retinal I/R injury.