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

Sujit S. Nair, Zhiyong Guo, Judith M. Mueller, Shahriar Koochekpour, Yun Qiu, Rajeshwar Rao Tekmal, Roland Schüle, Hsing Jien Kung, Rakesh Kumar, Ratna K. Vadlamudi

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)613-624
Number of pages12
JournalMolecular Endocrinology
Volume21
Issue number3
DOIs
Publication statusPublished - Mar 1 2007
Externally publishedYes

Fingerprint

Androgen Receptors
Estrogen Receptors
Proteins
src-Family Kinases
Cytoplasmic and Nuclear Receptors
human PELP1 protein
Transcriptional Activation
Prostatic Neoplasms
Small Interfering RNA
Prostate
Neoplasms
Yeasts

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Cite this

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. / Nair, Sujit S.; Guo, Zhiyong; Mueller, Judith M.; Koochekpour, Shahriar; Qiu, Yun; Tekmal, Rajeshwar Rao; Schüle, Roland; Kung, Hsing Jien; Kumar, Rakesh; Vadlamudi, Ratna K.

In: Molecular Endocrinology, Vol. 21, No. 3, 01.03.2007, p. 613-624.

Research output: Contribution to journalArticle

Nair, Sujit S. ; Guo, Zhiyong ; Mueller, Judith M. ; Koochekpour, Shahriar ; Qiu, Yun ; Tekmal, Rajeshwar Rao ; Schüle, Roland ; Kung, Hsing Jien ; Kumar, Rakesh ; Vadlamudi, Ratna K. / 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. In: Molecular Endocrinology. 2007 ; Vol. 21, No. 3. pp. 613-624.
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AU - Tekmal, Rajeshwar Rao

AU - Schüle, Roland

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AU - Kumar, Rakesh

AU - Vadlamudi, Ratna K.

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