The p53 tumor suppressor exerts anti-proliferative effects, including growth arrest, apoptosis, and cell senescence, in response to various types of stress. Mutations within the p53 gene have been well documented in more than half of all human tumors. Accumulating evidence further indicates that in tumors that retain wild-type p53, other defects in the p53 pathway also play an important role in cancer formation. As the center mediator of the pathway, although p53 is critically regulated by post-translational modifications and protein stability, subcellular localization of p53 also appears to play an important role in the regulation of p53 function. However, p53 is diffusely distributed in normal unstressed cells and in response to DNA damage and other types of stress, p53 translocates to the nucleus where it activates endogenous target genes. Thus, nuclear localization of p53 is essential for its function as a transcription factor. Recently, we have identified Pare, a Parkin-like ubiquitin ligase, as a cytoplasmic anchor protein for p53 in cells. Pare directly interacts, and forms a ~1 MDa complex, with p53 in the cytoplasm of unstressed cells. In the absence of stress, inactivation of Pare induces nuclear localization of endogenous p53 and activates p53-dependent apoptosis. Overexpression of Pare promotes cytoplasmic sequestration of ectopic p53. Furthermore, Pare is highly expressed in a number of neuroblastoma cell lines, where abnormal cytoplasmic localization of p53 was observed; RNAi-mediated reduction of endogenous Pare significantly sensitizes these neuroblastoma cells in the DNA damage response. Thus, our findings reveal that Pare is a critical regulator in controlling p53 subcellular localization and subsequent function. The overall objective of this project is to demonstrate the precise role of Pare in the regulation of p53 function, and to elucidate this novel p53 regulatory pathway in the stress response. The 1st specific aim is to identify novel regulatory factors associated with Pare. We will purify and identify of Parc associated protein complexes in human cells and examine the functional consequences of these novel interactions. The second specific aim is to define the physiological role of Pare in vivo. We will develop a mouse model by overexpression of Pare in vivo to assess its potential role in tumorigenesis, and will also use the targeted mutagenesis approach to establish the essential role of Pare in the regulation of p53 function in vivo.
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