Zhang J, Yan W, Chen X
Department of Cell Biology, The University of Alabama at Birmingham, Birmingham, 1530 3rd Avenue South, AL 35294-0005, USA.
Cell Death Differ. 2006 Dec;13(12):2118-28. doi: 10.1038/sj.cdd.4401972. Epub 2006 May 26.
p53 is necessary for the elimination of neural cells inappropriately differentiated or in response to stimuli. However, the role of p53 in neuronal differentiation is not certain. Here, we showed that nerve growth factor (NGF)-mediated differentiation in PC12 cells is enhanced by overexpression of wild-type p53 but inhibited by mutant p53 or knockdown of endogenous wild-type p53, the latter of which can be rescued by expression of exogenous wild-type p53. Interestingly, p53 knockdown or overexpression of mutant p53 attenuates NGF-mediated activation of TrkA, the high-affinity receptor for NGF and a tyrosine kinase, and activation of the mitogen-activated protein kinase pathway. In addition, p53 knockdown reduces the constitutive levels of TrkA, which renders PC12 cells inert to NGF. And finally, we showed that both constitutive and stimuli-induced expressions of TrkA are regulated by p53 and that induction of TrkA by activated endogenous p53 enhances NGF-mediated differentiation. Taken together, our data demonstrate that p53 plays a critical role in NGF-mediated neuronal differentiation in PC12 cells at least in part via regulation of TrkA levels.
p53对于消除分化不当或对刺激产生反应的神经细胞是必要的。然而，p53在神经元分化中的作用尚不确定。在此，我们表明，野生型p53的过表达增强了PC12细胞中神经生长因子（NGF）介导的分化，但突变型p53或内源性野生型p53的敲低则抑制了这种分化，后者可通过外源性野生型p53的表达得以挽救。有趣的是，p53的敲低或突变型p53的过表达减弱了NGF介导的TrkA激活，TrkA是NGF的高亲和力受体且为一种酪氨酸激酶，同时也减弱了丝裂原活化蛋白激酶途径的激活。此外，p53的敲低降低了TrkA的组成水平，这使得PC12细胞对NGF无反应。最后，我们表明TrkA的组成型表达和刺激诱导表达均受p53调控，并且内源性p53激活诱导的TrkA增强了NGF介导的分化。综上所述，我们的数据表明p53至少部分通过调节TrkA水平在PC12细胞中NGF介导的神经元分化中起关键作用。
