| ERK, a neuroprotective protein, involve s in stress response of nerve cellsfollowing ischemia. ERK is regulated by ma ny factors, but the upstream molecularmecha nisms involved are not fully understood .Objectives: To study the molecular mecha nism underlying Src-induce d up-regulationof the neuroprotective extracellula r-signa l-regulated kinase (ERK) and its targettranscription factors, such as CREB and ERα, through inhibition of PP2A activity,and offer a new therapeutic approach to the treatment of diseases caused by cerebralischemia.Methods: Clean grade adult healthy SD ma le rats was used. Rats were surgica llyprepared for four-vessel occlusion (4-VO), and the next day administrated with Srcinhibitor SU and PP2A inhibitor Ct respectively. After 20 min, rats underwent 10minischemia followed by different reperfusion time (0, 10′, 1h, 6h and 24h). Theseparated hippoca mpus was homogenized and proteins were extracted. Western blotor phospha tase activity assay kit was taken for activities of PP2A, Src/ERK cascade,and related downstream proteins (ERK/CREB/ERα).Results: 1. Biphasic activation of ERK induced by cerebral ischemia contributes tothe changed in activity of CREB and ERα. 2. Src inhibitor decreases activity of theERK/CREB and ERαpathways in hippoca mpi post-ischemia. 3. PP2A activityreaches a clima x accompanied by dephosphorylation of PP2A at approxima tely 1 hreperfusion post-ischemia , and Src activation is correla ted with an increase in PP2Aphosphorylation and inhibition following cerebral ischemia. 4. Inhibition of Src activity increase s PP2A activity in response to cerebral ischemia. 5. Src up-regulatesERK/CREB and ERαthrough inhibition of PP2A following cerebral ischemiConclusion: Src induces up-regulation of ERK activity and its target transcriptionfactors, CREB and ERα, through attenuation of PP2A activity and enhance theneuroprotective signa ling pathway... |
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