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PROLINE-, GLUTAMIC ACID-, AND LEUCINE-RICH PROTEIN 1; PELP1

PROLINE-, GLUTAMIC ACID-, AND LEUCINE-RICH PROTEIN 1; PELP1

Alternative titles; symbolsMNARHGNC Approved Gene Symbol: PELP1Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:4,669,773-4,704,136 (from NCBI)...

Alternative titles; symbols

  • MNAR

HGNC Approved Gene Symbol: PELP1

Cytogenetic location: 17p13.2 Genomic coordinates (GRCh38): 17:4,669,773-4,704,136 (from NCBI)

▼ Description
PELP1 is a coactivator of estrogen receptor (see ESR1; 133430)-mediated transcription and a corepressor of other nuclear hormone receptors and sequence-specific transcription factors (Choi et al., 2004). PELP1 also functions in a nucleolar protein complex that has a critical role in ribosomal RNA (rRNA) biogenesis (Castle et al., 2012).

▼ Cloning and Expression
Vadlamudi et al. (2001) cloned PELP1 by screening a HeLa cell cDNA library using a nucleotide probe based on the peptide sequence of purified PELP1. The deduced 1,282-amino acid protein contains an N-terminal domain with 9 LxxLL motifs, followed by 2 central cysteine-rich regions, which are separated by a nuclear localization signal, and 2 C-terminal proline-rich regions, which are separated by an acidic region. The 2 cysteine-rich regions may form 3 zinc fingers. PELP1 also contains several consensus phosphorylation sites. RNA dot blot analysis detected PELP1 expression in most tissues tested, with highest expression in testis, mammary gland, brain, skeletal muscle, and lung. Western blot analysis detected endogenous PELP1 at an apparent molecular mass of 160 kD in a human mammary carcinoma cell line. PELP1 localized predominantly in the nuclear fraction of fractionated cells, but some PELP1 also associated with the cytosolic fraction. Immunohistochemical analysis of several mouse tissues detected a tissue-specific distribution of Pelp1 in nuclei and cytoplasm. Western blot analysis of developing mouse mammary glands showed significantly higher staining during pregnancy and lower staining during lactation.

▼ Gene Function
Vadlamudi et al. (2001) demonstrated that PELP1 is a coactivator of ESR1. PELP1 interacted with ESR1 in a ligand-dependent manner, and deletion constructs indicated that the LxxLL motifs of PELP1 were required for the interaction. PELP1 enhanced 17-beta-estradiol-dependent transcriptional activation from the estrogen response element in a dose-dependent manner. PELP1 also interacted with the general transcriptional coactivators p300 (EP300; 602700) and CREB-binding protein (CREBBP; 600140).

Balasenthil and Vadlamudi (2003) found that overexpression of PELP1 hypersensitized breast cancer cells to 17-beta-estradiol signaling, leading to persistent hyperphosphorylation of RB1 (614041) on ser807 and ser821 and enhanced progression of breast cancer cells to S phase. PELP1 interacted with the C-terminal pocket domain of RB, and PELP1-RB interactions were required for PELP1-mediated maximal estrogen receptor coactivation functions, such as cyclin D1 (CCND1; 168461) induction. Balasenthil and Vadlamudi (2003) concluded that PELP1 contributes to 17-beta-estradiol-mediated G1/S phase progression in addition to its role in estrogen receptor transcriptional regulation.

Choi et al. (2004) determined that PELP1 functions as a corepressor of some nuclear hormone receptors and several sequence-specific transcription factors, such as AP1 (165160), TCF (see 142410), GCCR (138040), NUR77 (NR4A1; 139139), and NFKB (see 164011). Mutation analysis indicated that transcriptional repression required both the N-terminal leucine-rich region and the C-terminal glutamic acid-rich regions of PELP1, which were associated with HDAC2 (605164) and hypoacetylated core histones, respectively. Choi et al. (2004) concluded that PELP1 belongs to a class of corepressors that suppress histone acetylation via active deacetylation, using associated HDAC and masking core histones from acetylation by histone acetyltransferases.

Mishra et al. (2004) found that the PELP1 promoter was upregulated by both ESR1 and ESR2 (601663). PELP1 expression was differentially regulated by selective estrogen receptor modulators in a cell line-dependent manner. Mishra et al. (2004) concluded that PELP1 is an estrogen receptor target gene.

Using Western blot analysis, Kashiwaya et al. (2010) found that TTLL4 (618738) polyglutamylated PELP1 at its glutamate-rich stretch region, thereby enhancing cell growth. Polyglutamylated PELP1 interacted with histone H3 (see 602810) and was involved in chromatin remodeling. Furthermore, PELP1 interacted with 2 components of the MLL1 (KMT2A; 159555)-WDR5 (609012) complex, SENP3 (612844) and LAS1L (300964), and polyglutamylation of PELP1 by TTLL4 appeared to regulate these interactions.

Castle et al. (2012) showed that LAS1L formed an endogenous nucleolar complex with PELP1, TEX10 (616717), WDR18, NOL9, and SENP3 in human cell lines. All proteins in the complex cofractionated with the pre-60S ribosomal particle and with a particle containing the 32S rRNA intermediate, suggesting that they may be involved in processing of rRNA internal transcribed spacer-2 (ITS2), which is found in pre-32S rRNA. The proteins appeared to form separate complexes when not associated with preribosomal particles. Knockdown of any of the complex components via small interfering RNA reduced processing of 32S pre-rRNA to mature 28S rRNA and caused G1 arrest through stabilization of p53 (TP53; 191170). LAS1L and PELP1 were sumoylated with SUMO3 (602231), and depletion of the SUMO proteinase SENP3 or its interacting partner NPM1 (164040) increased sumoylation of LAS1L and PELP1 and caused their relocalization from nucleolus to nucleoplasm. Inhibition of RNA polymerase I (see 616404) did not affect assembly of the LAS1L- and PELP1-containing complex or interaction of NPM1 with PELP1, but it reduced the nucleolar localization of the complex. Castle et al. (2012) proposed that PELP1 may regulate polymerase I- or II (see 180660)-specific RNA processing events depending upon its subcellular compartment.

DNA damage results in acetylation of lysines in the C-terminal domain of the proapoptotic transcriptional activator p53. Wang et al. (2016) found that acidic domain-containing proteins, including SET (600960), DAXX (603186), PELP1, and VPRBP (DCAF1; 617259), bound the deacetylated C-terminal domain of p53 in human cell lines and repressed p53 function. SET, VPRBP, DAXX, and PELP1 also interacted with the deacetylated, but not acetylated, lysine-rich domain of histone H3.

▼ Gene Structure
Mishra et al. (2004) determined that the promoter region of the PELP1 gene contains binding sites for AP1 and SP1 (189906) and 2 half estrogen response elements.

▼ Mapping
By genomic sequence analysis, Vadlamudi et al. (2001) mapped the PELP1 gene to chromosome 17. Balasenthil and Vadlamudi (2003) refined the mapping of the PELP1 gene to chromosome 17p13.3.

Tags: 17p13.2