title: Increased phosphorylation of protein kinase B and related substrates after traumatic brain injury in humans and rats.
abstract: Activation of protein kinase B (PKB, also known as Akt) by phosphorylation at serine-473 and threonine-308 promotes cell survival in multiple in vitro and in vivo models where neuronal death is seen, including traumatic brain injury (TBI); however, whether PKB is activated in humans after TBI was heretofore unknown. Activated PKB inhibits apoptogenic factors and is involved in the regulation of several transcription factors. Accordingly, we examined phosphorylation of the PKB signaling pathway in humans as well as rats after TBI using phosphospecific antibodies. Increased phosphorylation of PKB and PKB substrates was detected in injured brain from both humans and rats. In humans, increased phosphorylation of the PKB signaling pathway-related proteins Bad and forkhead transcription factor (FKHR) was detected in patients with TBI versus controls. In rats, increased phosphorylation of FKHR, inhibitor of kappaBalpha, and cyclic adenosine monophosphate responsive element binding protein (CREB) was detected after TBI versus controls. The deoxyribonucleic acid-binding activity of CREB was also enhanced after TBI in rats. Increased phosphorylation of PKB and PKB substrates was identified in neurons and other cell types by immunohistochemistry in both humans and rats. These data show increased phosphorylation of PKB, PKB substrates, and related proteins after both experimental and clinical TBI, suggesting either activation of the PKB signaling pathway or reduced phosphatase activity in both species.
authors.affiliation: Department of Critical Care Medicine, The Safar Center for Resuscitation Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennyslvania 15260, USA.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Yaming
authors.initials: Y
authors.lastname: Chen
authors.forename: Milos D
authors.initials: MD
authors.lastname: Ikonomovic
authors.forename: Paula D
authors.initials: PD
authors.lastname: Nathaniel
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Kochanek
authors.forename: Donald W
authors.initials: DW
authors.lastname: Marion
authors.forename: Steven T
authors.initials: ST
authors.lastname: DeKosky
authors.forename: Larry W
authors.initials: LW
authors.lastname: Jenkins
authors.forename: Robert S B
authors.initials: RS
authors.lastname: Clark
mesh_terms: D000328:Adult; D000818:Animals; D001930:Brain Injuries / Q000201:enzymology / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000502:physiology; D013997:Time Factors; D051025:bcl-Associated Death Protein / Q000378:metabolism*
chemical_list: C494819:BAD protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D051858:Forkhead Transcription Factors; D020672:I-kappa B Proteins; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D051025:bcl-Associated Death Protein; D000072000:NF-KappaB Inhibitor alpha; D051057:Proto-Oncogene Proteins c-akt