A novel role for serum response factor in neuronal survival.
Recent studies indicate that neuroprotection afforded by brain-derived neurotrophic factor (BDNF) is mediated by extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinase (PI3K). However, the mechanisms by which ERK and PI3K exert neuroprotection are not completely understood. Because ERK1/2 and PI3K both stimulate serum response element (SRE)-mediated gene expression, and serum response factor (SRF) is indispensable for SRE-mediated transcription, we investigated whether SRF contributes to ERK1/2 and PI3K neuroprotection. To accomplish this goal, we used an established experimental paradigm in which BDNF protects postnatal cortical neurons against both trophic deprivation and camptothecin-induced DNA damage. BDNF protection against camptothecin is mediated primarily by ERK1/2 activation, whereas its protection against trophic deprivation is mainly through stimulation of the PI3K pathway (Hetman et al., 1999). Here we demonstrate that expression of a wild-type SRF is sufficient to protect postnatal cortical neurons against camptothecin or trophic deprivation. Expression of a dominant-negative SRF partially reversed BDNF neuroprotection against both apoptotic insults. Moreover, the dominant-negative SRF inhibited neuroprotection against trophic withdrawal afforded by expression of a constitutive active PI3K. In addition, protection against camptothecin by expression of constitutive active mitogen-activated protein kinase kinase 1, an upstream kinase that activates ERK1/2, was also blocked by expression of the dominant-negative SRF. These data suggest that SRF is both necessary and sufficient for BDNF neuroprotection of cortical neurons against trophic deprivation and DNA damage. Our data provide a direct demonstration of a biological function of SRF in neurons and a novel downstream neuroprotective mechanism common to both ERK1/2 and PI3K pathways.
Department of Environmental and Occupational Health Sciences, Graduate Program in Neurobiology and Behavior, Graduate Program in Molecular and Cell Biology, University of Washington, Seattle, Washington 98195-7234, USA.
Sandra H
SH
Chang
Steve
S
Poser
Zhengui
Z
Xia
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002166:Camptothecin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004249:DNA Damage / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D005799:Genes, Dominant; D048369:MAP Kinase Kinase 1; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020929:Mitogen-Activated Protein Kinase Kinases / Q000096:biosynthesis / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D026362:Serum Response Factor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D018696:Neuroprotective Agents; D026362:Serum Response Factor; D019869:Phosphatidylinositol 3-Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D020929:Mitogen-Activated Protein Kinase Kinases; D002166:Camptothecin