title: Immunohistochemical study of p53-associated proteins in rat brain following lithium-pilocarpine status epilepticus.
abstract: Activation of the p53-stress response pathway has been implicated in excitotoxic neuronal cell death. Recent studies have demonstrated an age-dependent induction of both p53 mRNA and protein in the rat brain following lithium-pilocarpine-mediated status epilepticus (LPSE). We investigated whether other proteins that have been shown to participate in the p53 cascade are induced by LPSE. We used immunohistochemistry to examine the expression of Mdm2, Bax, CD95/Fas/APO-1, ATM, Ref-1 and ubiquitin. A significant increase in nuclear Mdm2 immunoreactivity, which colocalized with p53, was observed in cells within hippocampal pyramidal cell layers, dentate gyrus, piriform cortex, amygdala and thalamus. Dual immunofluorescence microscopy revealed a reduction in free ubiquitin expression in cells with p53 and Mdm2 accumulation. Increased immunoreactivity for CD95/Fas/APO-1 and Bax was also detected in the same p53-positive cells. Moreover, expression of Ref-1 and ATM, which are involved in the response to oxidative stress-induced DNA damage and regulation of p53 function, were increased. Colocalization of Ref-1 and p53 suggests that Ref-1 might activate p53 function in LPSE-induced neurodegeneration. In contrast, ATM immunoreactivity was predominantly cytoplasmic suggesting that ATM may not directly modulate p53 activity in injured neurons. These results extend our previous observations with regard to activation and stabilization of p53 in injured central nervous system neurons. The data indicate that p53 induction following LPSE may activate downstream pro-apoptotic genes leading to neurodegeneration.
authors.affiliation: Department of Neurology, USC Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Zhiqun
authors.initials: Z
authors.lastname: Tan
authors.forename: Raman
authors.initials: R
authors.lastname: Sankar
authors.forename: Wenli
authors.initials: W
authors.lastname: Tu
authors.forename: Don
authors.initials: D
authors.lastname: Shin
authors.forename: Hantao
authors.initials: H
authors.lastname: Liu
authors.forename: Claude G
authors.initials: CG
authors.lastname: Wasterlain
authors.forename: Steven S
authors.initials: SS
authors.lastname: Schreiber
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D019757:Carbon-Oxygen Lyases / Q000378:metabolism; D018797:Cell Cycle Proteins; D016923:Cell Death / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase; D004268:DNA-Binding Proteins; D007150:Immunohistochemistry; D008094:Lithium / Q000494:pharmacology; D018721:Muscarinic Agonists / Q000494:pharmacology; D009410:Nerve Degeneration / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins; D010862:Pilocarpine / Q000494:pharmacology; D016548:Prosencephalon / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D051736:Proto-Oncogene Proteins c-mdm2; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013226:Status Epilepticus / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000378:metabolism
chemical_list: C494828:Bax protein, rat; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D018721:Muscarinic Agonists; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D010862:Pilocarpine; D008094:Lithium; C497208:Mdm2 protein, rat; D051736:Proto-Oncogene Proteins c-mdm2; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019757:Carbon-Oxygen Lyases; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase