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Linking Ras to p73

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Science's STKE  04 Apr 2006:
Vol. 2006, Issue 329, pp. tw113
DOI: 10.1126/stke.3292006tw113

p73 is related to the well-known tumor suppressor p53 both structurally and functionally: It contains sequences that resemble the p53 DNA binding, transactivation, and oligomerization domains; transcriptionally activates a subset of p53 target genes; and, like p53, can trigger cell cycle arrest and apoptosis. The oncogenic protein MDM2 (mouse double minutes 2) binds to both p53 and p73, thereby inhibiting the transcription of target genes (although through different mechanisms). Jeong et al. used a yeast two-hybrid screen to search a human brain cDNA library for proteins that bound p73 and identified p19ras, an alternative-splicing product of the proto-oncogene H-ras. An in vitro binding assay showed that the β isoform of p73 (p73β) bound to a protein containing p21ras amino acids 56 to 170 fused to glutathione S-transferase; moreover, both endogenous and overexpressed p73 and p21ras coimmunoprecipitated from HEK293 cells. Analysis of truncation mutants indicated that p21ras mainly bound to the p73β DNA binding domain. Unlike the more familiar H-ras product p21ras, p19ras is not targeted to the cell membrane, and it colocalized and interacted with p73β in the nucleus. When coexpressed, p19ras stimulated the transcription of a p73β target gene, an effect that depended on its ability to bind p73β. Moreover, p19ras bound MDM2, inhibited the interaction between p73β and MDM2, and blocked the ability of MDM2 to repress the transcription of p73β target genes. Thus, the authors have uncovered an unexpected link through which p19ras promotes p73-dependent signaling pathways.

M.-H. Jeong, J. Bae, W.-H. Kim, S.-M. Yoo, J.-W. Kim, P. I. Song, K.-H. Choi, p19ras interacts with and activates p73 by involving the MDM2 protein. J. Biol. Chem. 281, 8707-8715 (2006). [Abstract] [Full Text]

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