DeltaNp73 modulates nerve growth factor-mediated neuronal differentiation through repression of TrkA.
p73, a member of the p53 family, expresses two classes of proteins: the full-length TAp73 and the N-terminally truncated DeltaNp73. While TAp73 possesses many p53-like features, DeltaNp73 is dominant negative towards TAp73 and p53 and appears to have distinct functions in tumorigenesis and neuronal development. Given its biological importance, we investigated the role of DeltaNp73 in nerve growth factor (NGF)-mediated neuronal differentiation in PC12 cells. We show that overexpression of DeltaNp73alpha or DeltaNp73beta inhibits NGF-mediated neuronal differentiation in both p53-dependent and -independent manners. In line with this, we showed that the level of endogenous DeltaNp73 is progressively diminished in differentiating PC12 cells upon NGF treatment and knockdown of DeltaNp73 promotes NGF-mediated neuronal differentiation. Interestingly, we found that the ability of DeltaNp73 to suppress NGF-mediated neuronal differentiation is correlated with its ability to regulate the expression of TrkA, the high-affinity NGF receptor. Specifically, we found that DeltaNp73 directly binds to the TrkA promoter and transcriptionally represses TrkA expression, which in turn attenuates the NGF-mediated mitogen-activated protein kinase pathway. Conversely, the steady-state level of TrkA is increased upon knockdown of DeltaNp73. Furthermore, we found that histone deacetylase 1 (HDAC1) and HDAC2 are recruited by DeltaNp73 to the TrkA promoter and act as corepressors to suppress TrkA expression, which can be relieved by trichostatin A, an HDAC inhibitor. Taken together, we conclude that DeltaNp73 negatively regulates NGF-mediated neuronal differentiation by transrepressing TrkA.
Zhang
Jin
J
Center for Comparative Oncology, 2128 Tupper Hall, University of California at Davis, Davis, CA 95616, USA.
Chen
Xinbin
X
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D049109:Cell Proliferation; D005786:Gene Expression Regulation; D006655:Histone Deacetylases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D051381:Rats; D020917:Receptor, trkA / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
D009687:Nuclear Proteins; D020033:Protein Isoforms; D016159:Tumor Suppressor Protein p53; C454920:delta Np73, mouse; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D006655:Histone Deacetylases