Human Bcl-2 activates ERK signaling pathway to regulate activating protein-1, lens epithelium-derived growth factor and downstream genes

College of Life Sciences, Hunan Normal University, Changsha, PR China.
Oncogene (Impact Factor: 8.46). 10/2004; 23(44):7310-21. DOI: 10.1038/sj.onc.1208041
Source: PubMed


The proto-oncogene, bcl-2, has various functions besides its role in protecting cells from apoptosis. One of the functions is to regulate expression of other genes. Previous studies have demonstrated that Bcl-2 regulates activities of several important transcription factors including NF-kappaB and p53, and also their downstream genes. In our recent studies, we reported that Bcl-2 substantially downregulates expression of the endogenous alphaB-crystallin gene through modulating the transcriptional activity of lens epithelium-derived growth factor (LEDGF). In the present communication, we report that human Bcl-2 can positively regulate expression of the proto-oncogenes c-jun and c-fos. Moreover, it enhances the DNA binding activity and transactivity of the activating protein-1 (AP-1). Furthermore, we present evidence to show that Bcl-2 can also activate both ERK1 and ERK2 MAP kinases. Inhibition of the activities of these kinases or the upstream activating kinases by pharmacological inhibitors or dominant-negative mutants abolishes the Bcl-2-mediated regulation of AP-1, LEDGF and their downstream genes. Together, our results demonstrate that through activation of the ERK kinase signaling pathway, Bcl-2 regulates the transcriptional activities of multiple transcription factors, and hence modulates the expression of their downstream genes. Thus, our results provide a mechanism to explain how Bcl-2 may regulate expression of other genes.

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Available from: Yingwei Mao, Apr 04, 2014
    • "Just as BCL2 protein levels were lower in retinas of σR1 -/-mice compared with age-matched controls, so also were NF-κB (p50) levels reduced in σR1 -/-retinas compared with normal mice. ERK signaling is well known to regulate Bcl2 expression (Feng et al. 2004). Our studies have shown that levels of phosphorylated ERK1/2 (but not total ERK1/2) are reduced in the retinas of σR1 -/-mice compared with wildtype. "
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    ABSTRACT: Sigma receptor 1 (σR1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered to be a molecular chaperone. Marked protection against cell death has been observed when ligands for σR1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking σR1 (σR1 (-/-)) manifest late-onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of σR1 in the retina and the mechanisms by which its ligands afford neuroprotection are unclear. We therefore used σR1 (-/-) mice to investigate the expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1α) and proteins involved in apoptosis (BCL2, BAX) and to examine the retinal transcriptome at young ages. Whereas no significant changes occurred in the expression of major ER stress genes (over a period of a year) in neural retina, marked changes were observed in these genes, especially Atf6, in isolated retinal Müller glial cells. BCL2 levels decreased in σR1 (-/-) retina concomitantly with decreases in NFkB and pERK1/2. We postulate that σR1 regulates ER stress in retinal Müller cells and that the role of σR1 in retinal neuroprotection probably involves BCL2 and some of the proteins that modify its expression (such as ERK, NFκB). Data from the analysis of the retinal transcriptome of σR1 null mice provide new insights into the role of σR1 in retinal neuroprotection.
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    • "On the other hand, we did observe a large, significant increase in the anti-apoptotic protein, Bcl-2. This protein has previously been shown to decrease significantly following various toxic regimens of METH [89],[54], [90], and to be involved in various other preconditioning paradigms [20], [52], [53]. Thus, both our own findings and those previously reported by others suggest to us that Bcl-2 up regulation by low levels of METH acts to thwart the activation of pro-apoptotic pathways and to trigger the activation of pro-survival pathways in order to ultimately protect cells against higher levels of oxidative stress. "
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    ABSTRACT: Mild stress can protect against a larger insult, a phenomenon termed preconditioning or tolerance. To determine if a low intensity stressor could also protect cells against intense oxidative stress in a model of dopamine deficiency associated with Parkinson disease, we used methamphetamine to provide a mild, preconditioning stress, 6-hydroxydopamine (6-OHDA) as a source of potentially toxic oxidative stress, and MN9D cells as a model of dopamine neurons. We observed that prior exposure to subtoxic concentrations of methamphetamine protected these cells against 6-OHDA toxicity, whereas higher concentrations of methamphetamine exacerbated it. The protection by methamphetamine was accompanied by decreased uptake of both [(3)H] dopamine and 6-OHDA into the cells, which may have accounted for some of the apparent protection. However, a number of other effects of methamphetamine exposure suggest that the drug also affected basic cellular survival mechanisms. First, although methamphetamine preconditioning decreased basal pERK1/2 and pAkt levels, it enhanced the 6-OHDA-induced increase in these phosphokinases. Second, the apparent increase in pERK1/2 activity was accompanied by increased pMEK1/2 levels and decreased activity of protein phosphatase 2. Third, methamphetamine upregulated the pro-survival protein Bcl-2. Our results suggest that exposure to low concentrations of methamphetamine cause a number of changes in dopamine cells, some of which result in a decrease in their vulnerability to subsequent oxidative stress. These observations may provide insights into the development of new therapies for prevention or treatment of PD.
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    • "It is evident that, besides being able to block apoptotic signals, bcl-2 and bcl-xL share other important functions, such as the ability to transactivate transcription factors. It has been demonstrated that bcl-2 over-expression in experimental tumor models modulates the activity of several transcription factors including NF-kB, Activating Protein 1, Hypoxia Inducible factor 1 (HIF-1) and Sp1 (Chen et al. 2004; Feng et al. 2004; Trisciuoglio et al. 2004), not only in bcl-2- mediated inhibition of apoptosis but also in signaling pathways of angiogenesis, as we previously demonstrated, through the regulation of Hypoxia Inducible factor 1 (HIF-1) (Trisciuoglio et al. 2005b), or via the NF-kB pathway (Ricca et al. 2000; Karl et al. 2005). There is evidence supporting the capability of bcl-xL to modulate NF-kB transcriptional activity, exerting its anti-apoptotic function in normal human cells (Badrichani et al. 1999; Jiang and Clemens 2006) and cancer cells (Jang and Surh 2004). "
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    ABSTRACT: We recently reported that bcl-xL regulates interleukin 8 (CXCL8) protein expression and promoter activity in glioblastoma cells. In this paper we demonstrate that CXCL8 induction by bcl-xL is mediated through a nuclear factor-kappa B (NF-kB)-dependent mechanism. Mutational studies on the CXCL8 promoter showed that NF-kB binding site was required for bcl-xL-induced promoter activity and an enhanced nuclear expression of NF-kB subunits p65 and p50 was observed after bcl-xL over-expression. Electrophoretic mobility shift assay showed an increased DNA-binding activity of NF-kB in bcl-xL over-expressing cells and the use of specific antibodies confirmed the involvement of p65 and p50 in NF-kB activity on CXCL8 promoter sequence. NF-kB activity regulation by bcl-xL involved IkBalpha and IKK complex signaling pathway. In fact, bcl-xL over-expression induced a decrease of cytoplasmic expression of the IkBalpha protein, paralleled by an increase in the phosphorylation of the same IkBalpha and IKKalpha/beta. Moreover, the down-regulation of the ectopic or endogenous bcl-xL expression through RNA interference confirmed the ability of bcl-xL to modulate NF-kB pathway, and the transient expression of a degradation-resistant form of the cytoplasmic NF-kB inhibitor IkBalpha in bcl-xL transfectants confirmed the involvement of that inhibitor in bcl-xL-induced CXCL8 expression and promoter activity. In conclusion, our results demonstrate the role of NF-kB as the mediator of bcl-xL-induced CXCL8 up-regulation in glioblastoma cells.
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