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Papers In Press, published online ahead of print November 23, 2004
Department of Pharmacology, Case Western Reserve University, Cleveland, OH 44106
Corresponding Author: dxd49{at}po.cwru.edu
Androgen receptor-associated protein 55 (ARA55) belongs to LIM protein superfamily, which is featured by three or four N-terminal LD motifs and four C-terminal zinc finger-like LIM domains. Both LD motifs and LIM domains can serve as protein-protein interaction interfaces. Recently, we found that enforced expression of ARA55 inhibits transforming growth factor (TGF)-beta-mediated upregulation of Smad Binding Element (SBE)-luciferase reporter activity in NRP-154, and NRP-152 rat prostate and LNCaP human prostate cell lines. Moreover, ARA55 also inhibits induction of SBE4BV-luciferase and 3TP-luciferase (a PAI-1 promoter construct) reporters by constitutively active Smad3 (CA-Smad3) in these cell lines. Co-immunoprecipitation studies suggest an interaction between ARA55 and either CA-Smad3 or wild-type Smad3 (WT Smad3) in HEK293 cells, which occurs through the MH2 domain of Smad3 and the C-terminus of ARA55, with WT Smad3 having stronger affinity than CA-Smad3 to ARA55. GST pull-down assay demonstrates that this interaction can occur in a cell-free system. These results are consistent with the luciferase data showing that the C-terminus of ARA55 is critical for suppression of Smad3 activity. Furthermore, using a mammalian two-hybrid system we confirmed that ARA55 interacts with the MH2 domain of Smad3 and suppresses CA-Smad3-induced transcriptional responses. In conclusion, these results support that ARA55 selectively intercepts TGF-beta signaling through an interaction of the LIM domain of ARA55 to the MH2 domain of Smad3.
J. Biol. Chem, 10.1074/jbc.M411575200
Submitted on October 12, 2004
Revised on November 23, 2004
Accepted on November 22, 2004
Novel function of ARA55/Hic-5 as a negative regulator of Smad3 signaling
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