Role of calpain-mediated p53 truncation in semaphorin 3A-induced axonal growth regulation.
Neurite outgrowth represents a critical stage in the correct development of neuronal circuitries, and is dependent on the complex regulation of actin filament and microtubule dynamics by intrinsic as well as extrinsic signals. Previous studies have implicated the tumor suppressor factor, p53, in the regulation of axonal outgrowth through a nontranscriptional effect involving local regulation of the Rho kinase signaling pathway that controls these dynamics. In the present study, we first showed that semaphorin 3A-induced growth cone collapse in cultured hippocampal neurons was associated with the partial truncation of phosphorylated p53, and that both effects were prevented by calpain inhibition with either m-calpain-specific siRNA or inhibitors. We further determined that semaphorin 3A-mediated calpain activation and growth cone collapse were associated with m-calpain phosphorylation and prevented by inhibition of MAPK, ERK, or p38. In vitro studies confirmed that p53 and especially phosphorylated p53 were partially truncated by calpain. Thus, our results indicate that semaphorin 3A-mediated growth cone collapse is mediated in part by m-calpain activation, possibly through MAPK-mediated phosphorylation, and the resulting truncation of phosphorylated p53, leading to Rho kinase activation and cytoskeletal reorganization. They provide a pathway by which extrinsic signals regulate axonal growth through activation of m-calpain and p53 truncation.
Qin
Qingyu
Q
Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA.
Liao
Guanghong
G
Baudry
Michel
M
Bi
Xiaoning
X
D000818:Animals; D001369:Axons / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D017353:Gene Deletion; D020439:Growth Cones / Q000378:metabolism; D020935:MAP Kinase Signaling System; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D040121:Semaphorin-3A / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C488217:Sema3a protein, mouse; D040121:Semaphorin-3A; D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D002154:Calpain; C449000:m-calpain