Regulation of rDNA Transcription by Proto-Oncogene PELP1

Abstract

BackgroundProline-, glutamic acid-, and leucine-rich protein (PELP1) is a novel nuclear receptor coregulator with a multitude of functions. PELP1 serves as a scaffolding protein that couples various signaling complexes with nuclear receptors and participates as a transcriptional coregulator. Recent data suggest that PELP1 expression is deregulated in hormonal cancers, and that PELP1 functions as a proto-oncogene; however, the mechanism by which PELP1 promotes oncogenesis remains elusive.Methodology/Principal FindingsUsing pharmacological inhibitors, confocal microscopy and biochemical assays, we demonstrated that PELP1 is localized in the nucleolus and that PELP1 is associated with the active ribosomal RNA transcription. Cell synchronization studies showed that PELP1 nucleolar localization varies and the greatest amount of nucleolar localization was observed during S and G2 phases. Using pharmacological compounds and CDK site mutants of PELP1, we found that CDK's activity plays an important role on PELP1 nucleolar localization. Depletion of PELP1 by siRNA decreased the expression of pre-rRNA. Reporter gene assays using ribosomal DNA (pHrD) luc-reporter revealed that PELP1WT but not PELP1MT enhanced the expression of reporter. Deletion of nucleolar domains abolished PELP1-mediated activation of the pHrD reporter. ChIP analysis revealed that PELP1 is recruited to the promoter regions of rDNA and is needed for optimal transcription of ribosomal RNA.Conclusions/SignificanceCollectively, our results suggest that proto-oncogene PELP1 plays a vital role in rDNA transcription. PELP1 modulation of rRNA transcription, a key step in ribosomal biogenesis may have implications in PELP1-mediated oncogenic functions.

The Histone Variant MacroH2A1 Regulates Target Gene Expression in Part by Recruiting the Transcriptional Coregulator PELP1

“…Additionally, PARP-1 has been shown to interact with nucleolar proteins and transcriptional coregulators (nucleolin and nucleophosmin) in a number of contexts (64)(65)(66). Recent studies have shown that PELP1 enhances ribosomal DNA (rDNA) transcription (67) and functions in a complex with WDR18, TEX10, and a nucleolar deSUMOylating enzyme to control rRNA processing and ribosome biogenesis (68). Most recently, macroH2A1 has been shown to repress rRNA gene transcription (69).…”

The social network of PELP1 and its implications in breast and prostate cancers

“…CDK phosphorylation of PELP1 allows PELP1 to localize to the nucleolus, where it regulates rDNA transcription. The inhibition of CDKs dramatically reduces the localization of PELP1 to the nucleolus and has been shown to decrease rDNA promoter activity (Gonugunta et al 2011). This indicates that PELP1 has an overarching role not only in SR-mediated gene regulation but also in cell division.…”

“…PELP1 has three nucleolar domains (Nuc1: amino acids 79-160; Nuc2: amino acids 423-489; and Nuc 3: amino acids 569-642), which are important not only for the nuclear and nucleolar localization of PELP1, but also for rRNA processing and the activation of rDNA transcription and subsequent ribosome biogenesis (Gonugunta et al 2011). PELP1 has a single RIX1 (rRNA processing/ribosome biogenesis) (amino acids 73-224) domain that enables complex formation with proteins IPI1 (TEX10), IPI3 (WDR18), and LASL1 and allows Rea1 AAA ATPase to associate with the 60S ribosomal subunit, a critical step in rRNA processing and ribosome assembly.…”

“…With respect to subcellular localization, PELP1 is expressed in both the nuclei and nucleoli of cells, but at lower amounts in the cytosol and plasma membrane (Vadlamudi et al 2001, Dou et al 2005, Gonugunta et al 2011. PELP1 is involved in several critical cellular functions, including DNA and histone modification, ribosome synthesis, and genomic and nongenomic signaling.…”

“…PELP1 may be classified as a scaffolding protein , and it serves as a 'mediator' for protein-protein interactions in different cellular processes such as cell cycle regulation, transcription, cytoskeletal and epigenetic modifications, and ribosome biogenesis (Choi et al 2004, 2011, Gonugunta et al 2011, Mann et al 2013. PELP1 is widely expressed in various tissues, with the highest levels being measured in the brains, testes, ovaries, and uteri of mice (Vadlamudi et al 2001).…”