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Molecular and Cellular Biology, May 2007, p. 3868-3880, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02112-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

{Delta}Np73 Modulates Nerve Growth Factor-Mediated Neuronal Differentiation through Repression of TrkA{triangledown}

Jin Zhang and Xinbin Chen*

Center for Comparative Oncology, University of California at Davis, Davis, California 95616, and Department of Cell Biology, University of Alabama at Birmingham, Birmingham, Alabama 35294

Received 10 November 2006/ Returned for modification 8 January 2007/ Accepted 6 March 2007

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}Np73ß 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.

* Corresponding author. Mailing address: Center for Comparative Oncology, 2128 Tupper Hall, University of California at Davis, Davis, CA 95616. Phone: (530) 754-8404. Fax: (530) 752-6042. E-mail: xbchen{at}ucdavis.edu

{triangledown} Published ahead of print on 12 March 2007.

Molecular and Cellular Biology, May 2007, p. 3868-3880, Vol. 27, No. 10
0270-7306/07/$08.00+0     doi:10.1128/MCB.02112-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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