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Submitted on June 29, 2006
Accepted on December 19, 2006
Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, TX, USA; Department of Microbiology and Immunology and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, LA, USA; Universitaets-Frauenklinik und Zentrale Klinische Forschung, Freiburg, Germany; Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA; Department of Biological Chemistry, University of California at Davis, Sacramento, California; The University of Texas MD Anderson Cancer Center, Houston, TX, USA
* To whom correspondence should be addressed. E-mail: vadlamudi{at}uthscsa.edu.
Proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) is a coregulator of multiple nuclear receptors. Molecular mechanisms of PELP1 function are not completely understood, but its expression is upregulated in hormonal-dependent cancers. Using a yeast two-hybrid screen, we found that four-and-a-half LIM-only protein 2 (FHL2) interacted with PELP1. FHL2 is a transcriptional regulator that associates with nuclear cofactors, including androgen receptors (AR), and contains an intrinsic activation domain. PELP1 and FHL2 interact in vitro, in vivo, and co-localize in the nuclear compartment. PELP1 interacts with FHL2 via LIM domains 3 and 4 and synergistically enhances the transcriptional activity of FHL2. Src kinase is required for PELP1-mediated enhancement of FHL2 functions, as knock down of Src kinase expression or function, abolished PELP1-mediated FHL2 activation functions. PELP1 interacted with androgen receptor (AR) and enhanced FHL2-mediated AR transactivation functions. PELP1 knock down by siRNA or PELP1 mutant, which lacks an activation domain, reduced FHL2-mediated AR transactivation. Biochemical analyses revealed a complex consisting of PELP1, FHL2, and AR in prostate cancer cells. PELP1/MNAR expression was elevated in high-grade prostate tumors. Our results suggest that PELP1 functions as a molecular adaptor, coupling FHL2 with nuclear receptors, and PELP1-FHL2 interactions may have a role in prostate cancer progression.
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