ΔNp73 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 Delta Np73. While TAp73 possesses many p53-like features, Delta Np73 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 Delta Np73 in nerve growth factor (NGF)-mediated neuronal differentiation in PC12 cells. We show that overexpression of Delta Np73 alpha- or Delta Np73 beta inhibits (NGF)-mediated neuronal differentiation in both p53-dependent and -independent manners. In line with this, we showed that the level of endogenous Delta Np73 is progressively diminished in differentiating PC12 cells upon NGF treatment and knockdown of Delta Np73 promotes NGF-mediated neuronal differentiation. Interestingly, we found that the ability of Delta Np73 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 Delta Np73 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 Delta Np73. Furthermore, we found that histone deacetylase 1 (HDAC1) and HDAC2 are recruited by Delta Np73 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 Delta Np73 negatively regulates NGF-mediated neuronal differentiation by transrepressing TrkA.