PELP1 is a reader of histone H3 methylation that facilitates oestrogen receptor‐α target gene activation by regulating lysine demethylase 1 specificity

Nair, Sujit S.; Nair, Binoj C.; Cortez, Valerie; Chakravarty, Dimple; Metzger, Eric; Schüle, Roland; Brann, Darrell W.; Tekmal, Rajeshwar Rao; Vadlamudi, Ratna K.

doi:10.1038/embor.2010.62

Cited by 95 publications

(114 citation statements)

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“…It will therefore be interesting to see whether PELP1 has a role in the apoptotic response of cells lacking p53 via E2F pathway and future studies are needed. PELP1 is known to modulate epigenetic changes at ER target gene promoters through histone modifiers like KDM1, 24 and we speculate that PELP1 recruited to p53 target gene promoters may perform similar functions at p53 target genes upon genomic stress. The results from our study imply that PELP1 may function with p53 in safeguarding the genome from various types of stresses.…”

Section: Resultsmentioning

confidence: 99%

“…For confocal analysis, ZR75 breast cancer cells cultured on glass coverslips were treated with DMSO or camptothecin for 2 h followed by fixation, permeabilization and co-stained with antibodies against PELP1 (red) and p53/pS15-p53 (green) and colocalization was analyzed by confocal microscopy as described previously. 24 Chromatin immunoprecipitation. The ChIP analysis was performed as described previously.…”

Section: Methodsmentioning

confidence: 99%

“…The ChIP analysis was performed as described previously. 24 In brief, model cells were grown in five 150 mm plates and after attaining a confluence of B75%, cells were irradiated with 10 Gy ionizing radiation and allowed to incubate at 371C for 1-2 h. Cells were then cross-linked using formaldehyde and quenched by glycine. The chromatin was isolated and subjected to immunoprecipitation using the indicated antibodies.…”

Section: Methodsmentioning

confidence: 99%

“…15,16 PELP1 functions as a coregulator for several nuclear receptors such as estrogen receptor (ER), androgen receptor (AR) and progesterone receptor (PR), and transcription factors such as STAT3, AP1 and E2F. [17][18][19] PELP1 associates with the chromatin 20 and interacts with histone-modifying complexes 17 including acetylases (CBP/P300), 21 methylases (SETDB1 and MLL1), 22,23 demethylases (KDM1) 24 and deacetylases (HDAC2 and MTA1). 17 It promotes cell proliferation by enhancing G1 to S phase progression via its interactions with the pRb/E2F pathway.…”

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confidence: 99%

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Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

et al. 2014

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, glutamic acid-and leucine-rich protein-1 (PELP1) is a scaffolding oncogenic protein that functions as a coregulator for a number of nuclear receptors. p53 is an important transcription factor and tumor suppressor that has a critical role in DNA damage response (DDR) including cell cycle arrest, repair or apoptosis. In this study, we found an unexpected role for PELP1 in modulating p53-mediated DDR. PELP1 is phosphorylated at Serine1033 by various DDR kinases like ataxia-telangiectasia mutated, ataxia telangiectasia and Rad3-related or DNAPKc and this phosphorylation of PELP1 is important for p53 coactivation functions. PELP1-depleted p53 (wild-type) breast cancer cells were less sensitive to various genotoxic agents including etoposide, camptothecin or c-radiation. PELP1 interacts with p53, functions as p53-coactivator and is required for optimal activation of p53 target genes under genomic stress. Overall, these studies established a new role of PELP1 in DDRs and these findings will have future implications in our understanding of PELP1's role in cancer progression. Cell Death and Differentiation (2014) 21, 1409-1418; doi:10.1038/cdd.2014.55; published online 2 May 2014 p53 is considered as the guardian of genomic integrity and has an important role in initiating cellular response to various genomic stresses such as cell cycle arrest, senescence, DNA repair and apoptosis.1,2 Loss of p53 or mutations in p53 is observed in 450% of the cases of all cancers.3-5 Stabilization of p53 upon genomic stress and activation of its transcription functions are vital for its central role in the DNA damage/ genomic stress response and in its tumor-suppressive functions.6,7 Upon genomic stress, p53 is stabilized and activated because of a decreased interaction with its E3-ligase MDM2.8 Activated p53 then upregulates expression of target genes, such as p21/WAF1, GADD45, PUMA and NOXA, all of which are important in the cellular decisions for cell cycle arrest or apoptosis. Post-translational modifications of p53, including phosphorylation, acetylation, ubiquitinylation and methylation, 10-12 and interactions with several cofactors 13,14 have a critical role in the p53-mediated transcriptional response to the DNA damage response (DDR). Proline-, glutamic acid-and leucine-rich protein-1 (PELP1), a large multi-domain protein, modulates a number of biological processes and several pathways including estrogen signaling, and cancer progression. 17 It promotes cell proliferation by enhancing G1 to S phase progression via its interactions with the pRb/E2F pathway.25 PELP1 localizes to the nucleolus and has an important role in ribosomal biogenesis.26 PELP1 signaling is also implicated in apoptosis and differentiation, and PELP1 functions as a coactivator of RXR homodimers and RXR-PPAR heterodimers.27 Although PELP1's role in both cell proliferation and differentiation is evident, it is not known how PELP1 would affect p53-mediated DDR functions and whether PELP1 status would affect sensitivity to various genomic stresses.In this study,...

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

et al. 2014

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“…H3K4me2 is a marker for gene activation and has been implicated in activation of the ERa target gene promoter (Nair et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Estrogen receptor-α, RBCK1, and protein kinase C β 1 cooperate to regulate estrogen receptor-α gene expression

Gustafsson

Heldring

Dahlman-Wright

2012

Journal of Molecular Endocrinology

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Estrogen receptor a (ERa) is initially overexpressed in two-thirds of all breast cancers and is involved in its development and proliferation. We previously reported that the RanBP-type and C3HC4-type zinc finger containing 1 (RBCK1) interacts with the ERa promoter and that RBCK1 expression positively correlates with ERa levels, expression of ERa downstream target genes, and proliferation of breast cancer cells. Based on this, and that RBCK1 positively correlates with ERa expression in breast cancer samples, we propose RBCK1 as a potential therapeutic target in breast cancer acting as a modulator of ERa expression. To further explore this, the molecular mechanism by which RBCK1 regulates ERa expression has to be defined. Here, we show that ERa, RBCK1, and the RBCK1-interacting protein protein kinase C b 1 (PKCb I ) co-occupy a previously identified ERa binding region in the proximal ERa promoter. We describe a number of mechanistic details of this complex including that RBCK1 recruitment to the ERa promoter B is facilitated by ERa, which in turn facilitates PKCb I recruitment and PKCb I -dependent histone modifications. Furthermore, ERa regulation of its own mRNA expression is facilitated by RBCK1 recruitment, suggesting an ERa coactivator function of RBCK1. The interaction between RBCK1 and ERa was dependent on the E3 ubiquitin ligase domain of RBCK1 and the activating function-1 domain of ERa. The ligand-binding function of ERa does not influence the interaction with RBCK1. In summary, our data provide insight into the molecular mechanism by which ERa expression is modulated in breast cancer cells.

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Interaction of transcription factor AP‐2 gamma with proto‐oncogene PELP1 promotes tumorigenesis by enhancing RET signaling

Liu

et al. 2021

Molecular Oncology

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Transcription factor AP‐2 gamma (TFAP2C) is a known regulator of the estrogen receptor, and high expression of TFAP2C is associated with therapy resistance. This study identified PELP1 as a TFAP2C interacting protein. PELP1 is essential for optimal TFAP2C transcriptional functions. TFAP2C interactions with PELP1 confer a growth advantage to breast cancer (BC) cells by activating an oncogenic RET signaling thus contributing to BC progression and therapy resistance.

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PELP1 is a reader of histone H3 methylation that facilitates oestrogen receptor‐α target gene activation by regulating lysine demethylase 1 specificity

Cited by 95 publications

References 16 publications

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response

Estrogen receptor-α, RBCK1, and protein kinase C β 1 cooperate to regulate estrogen receptor-α gene expression

Interaction of transcription factor AP‐2 gamma with proto‐oncogene PELP1 promotes tumorigenesis by enhancing RET signaling

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