Proline-, glutamic acid-, and leucine-rich protein-1/modulator of nongenomic activity of estrogen receptor enhances androgen receptor functions through LIM-only coactivator, four-and-a-half LIM-only protein 2.
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 up-regulated 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 (ARs), and contains an intrinsic activation domain. PELP1 and FHL2 interact in vitro and in vivo and colocalize 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 because knockdown of Src kinase expression or function abolished PELP1-mediated FHL2 activation functions. PELP1 interacted with AR and enhanced FHL2-mediated AR transactivation functions. PELP1 knockdown by small interfering RNA 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.
Nair
Sujit S
SS
Department of Obstetrics and Gynecology, University of Texas Health Science Center, Floyd Curl Drive, San Antonio, Texas 78229-3900, USA.
Guo
Zhiyong
Z
Mueller
Judith M
JM
Koochekpour
Shahriar
S
Qiu
Yun
Y
Tekmal
Rajeshwar Rao
RR
Schüle
Roland
R
Kung
Hsing-Jien
HJ
Kumar
Rakesh
R
Vadlamudi
Ratna K
RK
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D056970:Co-Repressor Proteins; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D060850:LIM-Homeodomain Proteins; D008297:Male; D051379:Mice; D009124:Muscle Proteins / Q000378:metabolism / Q000502:physiology*; D041681:NIH 3T3 Cells; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology; D025941:Protein Interaction Mapping; D011944:Receptors, Androgen / Q000502:physiology*; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured
D056970:Co-Repressor Proteins; C105987:FHL2 protein, human; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D009124:Muscle Proteins; C438485:PELP1 protein, human; D011944:Receptors, Androgen; D015534:Trans-Activators; D014157:Transcription Factors