Out accelerating aging. Previous research from our laboratory found p53 overexpressed and oxidatively modified by oxidative and nitrosative stress in brain from subjects with mild cognitive impairment (MCI) and AD brain, compared to control samples [26,27]. Conformational alterations of p53 in MCI and AD are known [19]. These observations are consistent with the role played by p53 in neuronal death detected in neurodegenerative conditions, and with an important link of p53 with oxidative stress. ROS and p53 appear to be interconnected at multiple levels in their signaling pathways. First, ROS are potent activators of p53, acting in different ways such as damaged 12926553 DNA, and even by regulating the redox status of cysteines present in the DNA-binding domain of p53, affecting its DNA-binding activity [26,28,29]. Moreover, once activated p53 generates downstream ROS which mediate apoptosis [12,30]. Therefore p53 appears to regulate cellular redox status [11]. Since oxidative stress has been considered a crucial factor that contributes to neurodegenerative processes like AD [31?3], p53 could be a therapeutic target to reduce the levels of ROS, and in this way prevent or attenuate neuronal death in neurodegenerative disorders such as MCI and AD. In a previous study, we demonstrated for the first time that the lack of p53 significantly decreases basal levels of oxidative and nitrosative stress in mice brain, and that this loss of p53 could activate diverse protective pathways involved in maintaining cellular homeostasis in the brain of p53(2/2) mice [20]. In the present study using proteomics, we gained insight into the role of p53 in the CNS, and tested the hypothesis that knock out of p53 affected the expression of several brain mitochondrial proteins involved in different pathways; thus, loss of p53 may present aChaperone proteinsHeat shock cognate (HSC)-71, a member of the Hsp70 family of proteins [44], was found up-regulated in the mitochondrial fraction isolated from the brain of p53(2/2) mice compared to WT. Previously, Agoff 23727046 [45] established that Hsp70 is repressed by p53, corroborating our result. The Hsp family acts as chaperones assuring proper folding and assembly of proteins, and protects cells against apoptosis [46]. This latter function is prominently carried out by Hsp70. It is conceivable that the Hsp family exerts a crucial role in neuronal death linked with neurodegenerative disorders. HSC-71 is the (��)-Imazamox manufacturer constitutive isoform of the Hsp 70, activated by cells in adverse conditions. This chaperone protein is involved in the degradation of damaged proteins shuttling them for proteolysis [47]. In AD, the expression of Hsps seems to have a protective function toProteomics of p53-Regulated Pathways in Brainprevent the formation of amyloid fibrils [48], and previously, HSC-71 was found down regulated [49], and oxidatively modified in AD brain [50]. Therefore the increase of HSC-71 expression levels, induced by the lack of p53, conceivably could play a protective role in AD progression.Energy dysfunction and mitochondrial alterationsSeveral findings suggest that p53 has a role in the regulation of pathways involved in glucose metabolism, supporting oxidative phosphorylation and the pentose phosphate shunt, and inhibiting glycolysis [11]. These activities of p53 prevent cancer development. In addition, mitochondria are a major site in which some K162 web constituents of these pathways play a role. Therefore, there is a connection between p53 and mito.Out accelerating aging. Previous research from our laboratory found p53 overexpressed and oxidatively modified by oxidative and nitrosative stress in brain from subjects with mild cognitive impairment (MCI) and AD brain, compared to control samples [26,27]. Conformational alterations of p53 in MCI and AD are known [19]. These observations are consistent with the role played by p53 in neuronal death detected in neurodegenerative conditions, and with an important link of p53 with oxidative stress. ROS and p53 appear to be interconnected at multiple levels in their signaling pathways. First, ROS are potent activators of p53, acting in different ways such as damaged 12926553 DNA, and even by regulating the redox status of cysteines present in the DNA-binding domain of p53, affecting its DNA-binding activity [26,28,29]. Moreover, once activated p53 generates downstream ROS which mediate apoptosis [12,30]. Therefore p53 appears to regulate cellular redox status [11]. Since oxidative stress has been considered a crucial factor that contributes to neurodegenerative processes like AD [31?3], p53 could be a therapeutic target to reduce the levels of ROS, and in this way prevent or attenuate neuronal death in neurodegenerative disorders such as MCI and AD. In a previous study, we demonstrated for the first time that the lack of p53 significantly decreases basal levels of oxidative and nitrosative stress in mice brain, and that this loss of p53 could activate diverse protective pathways involved in maintaining cellular homeostasis in the brain of p53(2/2) mice [20]. In the present study using proteomics, we gained insight into the role of p53 in the CNS, and tested the hypothesis that knock out of p53 affected the expression of several brain mitochondrial proteins involved in different pathways; thus, loss of p53 may present aChaperone proteinsHeat shock cognate (HSC)-71, a member of the Hsp70 family of proteins [44], was found up-regulated in the mitochondrial fraction isolated from the brain of p53(2/2) mice compared to WT. Previously, Agoff 23727046 [45] established that Hsp70 is repressed by p53, corroborating our result. The Hsp family acts as chaperones assuring proper folding and assembly of proteins, and protects cells against apoptosis [46]. This latter function is prominently carried out by Hsp70. It is conceivable that the Hsp family exerts a crucial role in neuronal death linked with neurodegenerative disorders. HSC-71 is the constitutive isoform of the Hsp 70, activated by cells in adverse conditions. This chaperone protein is involved in the degradation of damaged proteins shuttling them for proteolysis [47]. In AD, the expression of Hsps seems to have a protective function toProteomics of p53-Regulated Pathways in Brainprevent the formation of amyloid fibrils [48], and previously, HSC-71 was found down regulated [49], and oxidatively modified in AD brain [50]. Therefore the increase of HSC-71 expression levels, induced by the lack of p53, conceivably could play a protective role in AD progression.Energy dysfunction and mitochondrial alterationsSeveral findings suggest that p53 has a role in the regulation of pathways involved in glucose metabolism, supporting oxidative phosphorylation and the pentose phosphate shunt, and inhibiting glycolysis [11]. These activities of p53 prevent cancer development. In addition, mitochondria are a major site in which some constituents of these pathways play a role. Therefore, there is a connection between p53 and mito.
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