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)

Preconditioning adaptation induced by transient ischemia can increase brain tolerance to oxidative stress, but the underlying neuroprotective mechanisms are not fully understood. Recently, we developed a human brain-derived cell model to investigate preconditioning mechanism in SH-SY5Y neuroblastoma cells.(1) Our results demonstrate that a non-lethal serum deprivation-stress for 2 h (preconditioning stress) enhanced the tolerance to a subsequent lethal oxidative stress (24 h serum deprivation) and also to 1-methyl-4-phenyl-pyridinium (MPP(+)).(2) Two-hour non-lethal preconditioning stress increased the expression of neuronal nitric oxide (NOS1/nNOS) mRNA, Fos, Ref-1, NOS protein, and then nitric oxide (*NO) production. As well as MnSOD expression, the *NO-cGMP-PKG pathway mediated the preconditioning-induced upregulation of antiapoptotic protein Bcl-2 and the downregulation of adaptor protein p66(shc). We also propose that cGMP-mediated preconditioning-induced adaptation against oxidative stress may be due to the synthesis of a new protein, such as thioredoxin (Trx) since the protective effect can be blocked by Trx reductase inhibitor.(3) The antioxidative potency of Trx was approximately 100 and 1,000 times greater than GSNO and GSH, respectively. These results suggest that *NO-cGMP-PKG signaling pathway plays an important role in the preconditioning-induced neuroprotection, and perhaps cardioprotection, against oxidative stress.
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PMID:Preconditioning-mediated neuroprotection: role of nitric oxide, cGMP, and new protein expression. 1207 58

Accumulating evidence suggests that deregulated cyclin-dependent kinase 5 (Cdk5) plays a critical part in neuronal death. However, the pathogenic targets of Cdk5 are not fully defined. Here we demonstrate that the Cdk5 activator p35 interacts directly with apurinic/apyrimidinic endonuclease 1 (Ape1), a protein crucial for base excision repair (BER) following DNA damage. Cdk5 complexes phosphorylate Ape1 at Thr 232 and thereby reduces its apurinic/apyrimidinic (AP) endonuclease activity. Ape1 phosphorylation is dependent on Cdk5 in in vitro and in vivo. The reduced endonuclease activity of phosphorylated Ape1 results in accumulation of DNA damage and contributes to neuronal death. Overexpression of Ape1(WT) and Ape1(T232A), but not the phosphorylation mimic Ape1(T232E), protects neurons against MPP(+)/MPTP. Loss of Ape1 sensitizes neurons to death. Importantly, increased phosphorylated Ape1 was also observed in post-mortem brain tissue from patients with Parkinson's and Alzheimer's diseases, suggesting a potential link between Ape1 phosphorylation and the pathogenesis of neurodegenerative diseases.
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PMID:The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death. 2047 98

Oxidative stress, induced by reactive oxygen species (ROS), is an apoptosis activator. Oxidative stress causes dopaminergic neuron loss and plays a pivotal role in the pathogenesis of Parkinson's disease (PD). A recent study showed that apurinic/apyrimidinic endonuclease 1 (Ape1) decreases cytotoxicity and promotes neuron survival under oxidative stress. Furthermore, it has been proven that Ape1 is involved in the pathogenesis of PD. However, little is known about the contribution of Ape1 toward the development of PD. Thus, the present study was designed to define a critical pathway by which Ape1 mediates neurotoxicity in a model of PD. The results show that Ape1 was upregulated in MPP-treated PC12 cells. Ape1 overexpression significantly increased cell viability and inhibited apoptosis compared with MPP treatment, whereas Ape1 knockdown showed the opposite effect. Ape1 overexpression markedly suppressed ROS levels, whereas Ape1 knockdown significantly elevated ROS levels. Furthermore, Ape1 overexpression markedly upregulated the p-ERK1/2 protein expression level and inhibited ERK1/2 signaling. The ERK1/2 inhibitor PD98059 significantly decreased cell viability and increased apoptosis and the ROS level compared with the Ape1 overexpression group. Taken together, these results suggest that Ape1 protects against neuron death by activating the ERK1/2 signaling pathway.
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PMID:Ape1 protects against MPP+-induced neurotoxicity through ERK1/2 signaling in PC12 cells. 2789 8