Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.64 (MPP)
 1,876 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In an accompanying paper, we show that the mitochondrial Unfolded Protein Response or mtUPR is initiated by the activation of transcription of chop through an AP-1 element in the chop promoter. Further, we show that the c/ebp beta gene is similarly activated and CHOP and C/EBP beta subsequently hetero-dimerise to activate transcription of mtUPR responsive genes. Here, we report the discovery of six additional mtUPR responsive genes. We found that these genes encoding mitochondrial proteases YME1L1 and MPP beta, import component Tim17A and enzymes NDUFB2, endonuclease G and thioredoxin 2, all contain a CHOP element in their promoters. In contrast, genes encoding mitochondrial proteins Afg3L2, Paraplegin, Lon and SAM 50, which do not have a CHOP element, were not up-regulated. Conversely, genes with CHOP elements encoding cytosolic proteins were not induced by the accumulation of unfolded proteins in mitochondria. These results indicate that mtUPR responsive genes appear to share a requirement for a CHOP element, but that this is not sufficient for the regulation of the mtUPR. A more detailed analysis of promoters of mtUPR responsive genes revealed at least two additional highly conserved, putative regulatory sites either side of the CHOP element, one a motif of 12 bp which lies 14 bp upstream of the CHOP site and another 9 bp element, 2 bp downstream of the CHOP site. Both of these additional elements are conserved in the promoters of 9 of the ten mtUPR responsive genes we have identified so far, the exception being the Cpn60/10 bidirectional promoter. Mutation of each of these elements substantially reduced the mtUPR responsiveness of the promoters suggesting that these elements coordinately regulate mtUPR.
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PMID:Discovery of genes activated by the mitochondrial unfolded protein response (mtUPR) and cognate promoter elements. 1784 4

Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra with unknown etiology. Neuropathology seen in the brains of PD patients can be closely mimicked by MPP(+)-induced neurotoxicity in vitro. In this study, we used an S-type human neuroblastoma cell line (SH-EP1) as a model to investigate the involvement of NF-kappaB and JNK pathways in MPP(+)-induced neurotoxicity. We show that NF-kappaB was activated by MPP(+) as evidenced by NF-kappaB p65 nuclear translocation, the increased DNA binding activity and a rapid phosphorylation of NF-kappaB inhibitor (IkappaBalpha). NF-kappaB partially mediated the neurotoxicity of MPP(+), as suggested by the reduction of MPP(+)-induced cell death by both a specific IkappaB kinase (IKK) inhibitor and a dominant negative form of IkappaBalpha (IkappaBalpha-M). Besides NF-kappaB, JNK and c-Jun/AP-1 were also activated upon MPP(+) stimulation. Inhibition of JNK activation with a specific JNK inhibitor partially reduced the MPP(+)-mediated cell death. Similarly, inhibition of c-Jun/AP-1 activation, either by a dominant negative c-Jun or c-Jun/AP-1 inhibitor, significantly attenuated MPP(+)-mediated cell death. These results suggest that both JNK and c-Jun/AP-1 activation are pro-apoptotic. Furthermore, we provide clear evidence for the existence of a crosstalk between the NF-kappaB and JNK signaling as MPP(+)-induced activation of JNK and c-Jun/AP-1 was strongly down-regulated in IkappaBalpha-M cells. In conclusion, we demonstrate that in SH-EP1 cells MPP(+)-induced neurotoxicity is partially mediated by NF-kappaB which in turn acts on the activation of JNK and c-Jun/AP-1. These results may point to a combined inhibition of NF-kappaB and JNK as a new approach to PD therapy.
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PMID:NF-kappaB mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH-EP1 through JNK and c-Jun/AP-1. 1977 65

The aberrant expression of matrix metalloproteinases (MMPs) is known to play an important role in various neurodegenerative diseases, such as Parkinson's disease. In the present study, we found that two well-known dopaminergic neurotoxins, 6-OHDA and MPP(+), induced the expression of MMP-9 in SK-N-BE(2)C human neuroblastoma and Cath.a mouse dopaminergic cell lines. Treatment with MMP-9 inhibitors attenuated the neuronal cell death induced by either 6-OHDA or MPP(+), suggesting that MMP-9 plays an important role in this neurotoxin-mediated cell death. Further mechanistic studies showed that 6-OHDA and MPP(+) increased MMP-9 gene expression by inducing NF-kappaB and AP-1 binding to the MMP-9 promoter. Reactive oxygen species (ROS) appeared to be involved in MMP-9 expression because treatment with the free radical scavenger, N-acetylcysteine (NAC), suppressed both 6-OHDA- and MPP(+)-induced MMP-9 promoter activities. Treatment with several signaling pathway-specific inhibitors revealed that the PI3 kinase inhibitor, LY294002, suppressed 6-OHDA- and MPP(+)-induced MMP-9 promoter activities, whereas the p38 MAPK inhibitor, SB203580, inhibited 6-OHDA-, but not MPP(+)-induced promoter activity. These results collectively suggest that ROS, PI3 kinase, NF-kappaB, and AP-1 are commonly involved in 6-OHDA- and MPP(+)-induced MMP-9 gene expression, and that p38 MAPK is differentially involved. Therefore, controlling MMP-9 expression may have therapeutic potential in Parkinson's disease, which is caused by various neurotoxins, such as 6-OHDA and MPP(+).
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PMID:Regulation of matrix metalloproteinase-9 gene expression in MPP+- or 6-OHDA-treated human neuroblastoma SK-N-BE(2)C cells. 1996 14