Biology:PELP-1

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Short description: Mammalian protein found in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Proline-, glutamic acid- and leucine-rich protein 1 (PELP1) also known as modulator of non-genomic activity of estrogen receptor (MNAR) and transcription factor HMX3 is a protein that in humans is encoded by the PELP1 gene.[1] is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors[2] and a coactivator for estrogen receptors.[3]

Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is transcription coregulator and modulates functions of several hormonal receptors and transcription factors.[4][5] PELP1 plays essential roles in hormonal signaling, cell cycle progression, and ribosomal biogenesis.[6][7] PELP1 expression is upregulated in several cancers; its deregulation contributes to hormonal therapy resistance and metastasis; therefore, PELP1 represents a novel therapeutic target for many cancers.[8][9]

Gene

PELP1 is located on chromosome 17p13.2 and PELP1 is expressed in a wide variety of tissues; its highest expression levels are found in the brain, testes, ovaries, and uterus.[3][10][11][12] Currently, there are two known isoforms (long 3.8 Kb and short 3.4 Kb) and short isoform is widely expressed in cancer cells.[13]

Structure

The PELP1 protein encodes a protein of 1130 amino acids, and exhibits both cytoplasmic and nuclear localization depending on the tissue.[3] PELP1 lacks known enzymatic activity and functions as a scaffolding protein. It contains 10 NR-interacting boxes (LXXLL motifs)[3] and functions as a coregulator of several nuclear receptors via its LXXLL motifs including ESR1,[3] ESR2,[14] ERR-alpha,[15] PR,[16] GR,[2][17] AR,[18][19] and RXR.[20] PELP1 also functions as a coregulator of several other transcription factors, including AP1, SP1, NFkB,[2] STAT3,[21] and FHL2.[19]

PELP1 has a histone binding domain and interacts with chromatin-modifying complexes, including CBP/p300,[3] histone deacetylase 2,[2] histones,[2][22] SUMO2,[23] lysine-specific demethylase 1 (KDM1),[24] PRMT6,[25] and CARM1.[26] PELP1 also interacts with cell cycle regulators such as pRb.[13] E2F1,[27] and p53.[28]

PELP1 is phosphorylated by hormonal and growth factor signals.[29][30] PELP1 phosphorylation status is also influenced by cell cycle progression, and it is a substrate of CDKs.[31] Further, PELP1 is phosphorylated by DNA damage induced kinases (ATM, ATR, DNA-PKcs).[28]

Function

PELP1 functions as a coactivator of several NRs and regulates genes involved in proliferation and cancer progression. PELP1 enhances transcription functions of ESR1, ESR2, AR, GR, E2F and STAT3.[4][5][7] PELP1 participates in activation of ESR1 extra-nuclear actions[4][29] by coupling ESR1 with Src kinase[32] PI3K[33] STAT3 [21] ILK1 [32] and mTOR[34] PELP1 participates in E2-mediated cell proliferation and is a substrate of CDK4/cyclin D1, CDK2/cyclin E and CDK2/cyclin A complexes.[31] Studies using TG mice model suggested the existence of an autocrine loop involving the CDK–cyclin D1–PELP1 axis in promoting mammary tumorigenesis [35]

PELP1 has a histone binding domain; functions as a reader of histone modifications, interacts with epigenetic modifiers such as HDAC2, KDM1, PRMT6, CARM1; and facilitates activation of genes involved in proliferation and cancer progression.[2][22][24][25][26] PELP1 modulates the expression of miRs, PELP1-mediated epigenetic changes play important role in the regulation miR expression and many of PELP1 mediated miRS are involved in promoting metastasis.[36] PELP1 is needed for optimal DNA damage response, is phosphorylated by DDR kinases and is important for p53 coactivation function.[28] PELP1 also interacts with MTp53, regulates its recruitment, and alters MTp53 target gene expression. PELP1 depletion contributes to increased stability of E2F1.[27] PELP1 binds RNA, and participates in RNA splicing. The PELP1-regulated genome includes several uniquely spliced isoforms. Mechanistic studies showed that PELP1 interaction with the arginine methyltransferase PRMT6 plays a role in RNA splicing.[25]

PELP1 plays critical roles in 60S ribosomal subunit synthesis and ribosomal RNA transcription. The SENP3-associated complex comprising PELP1, TEX10 and WDR18 is involved in maturation and nucleolar release of the large ribosomal subunit.[37][38][39] SUMO conjugation/deconjugation of PELP1 controls its dynamic association with the AAA ATPase MDN1, a key factor of pre-60S remodeling. Modification of PELP1 promotes the recruitment of MDN1 to pre-60S particles, while deSUMOylation is needed to release both MDN1 and PELP1 from pre-ribosomes.[40]

PELP1 is widely expressed in many regions of brain, including the hippocampus, hypothalamus, and cerebral cortex. PELP1 interacts with ESR1, Src, PI3K and GSK3β in the brain. It is essential for E2-mediated extra-nuclear signaling following global cerebral ischemic.[6][10] PELP1 plays an essential role in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.[41] Ability of E2 to exert anti-inflammatory effects was lost in PELP1 forebrain-specific knockout mice, indicating a key role for PELP1 in E2 anti-inflammatory signaling.[42]

PELP1 is a proto-oncogene[43] that provides cancer cells with a distinct growth and survival advantage.[5][9] PELP1 interacts with various enzymes that modulate the cytoskeleton, cell migration, and metastasis.[43][44][45] PELP1 deregulation in vivo promotes development of mammary gland hyperplasia and carcinoma [35] PELP1 is implicated in progression of breast,[27][34][43][46] endometrial,[14] ovarian,[33] salivary[47] prostate,[18][19] lung,[48] pancreas,[49] and colon[50] neoplasms.

PELP1 signaling contributes to hormonal therapy resistance.[4][9][51] Altered localization of PLP1 contributes to tamoxifen resistance via excessive activation of the AKT pathway [29][52] and cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of tamoxifen.[53] AR, PELP1 and Src form constitutive complexes in prostate neoplasms model cells that exhibit androgen independence.[54] Cytoplasmic localization of PELP1 upregulates pro-tumorigenic IKKε and secrete inflammatory signals, which through paracrine macrophage activation, regulate the migratory phenotype associated with breast cancer initiation.[55]

Clinical significance

PELP1 is a proto-oncogene that provides cancer cells with a distinct growth and survival advantage. PELP1 overexpression has been reported in many cancers. PELP1 expression is an independent prognostic predictor of shorter breast cancer–specific survival and disease free interval.[56] Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen [52] and PELP1 deregulated tumors respond to Src kinase[51] and mTOR inhibitors.[34] Treatment of breast and ovarian cancer xenografts with liposomal PELP1–siRNA–DOPC formulations revealed that knockdown of PELP1 significantly reduce the tumor growth.[33][57] These results provided initial proof that PELP1 is a bonafide therapeutic target. Emerging data support a central role for PELP1 and its direct protein–protein interactions in cancer progression. Since PELP1 lacks known enzymatic activity, drugs that target PELP1 interactions with other proteins should have clinical utility. Recent studies described an inhibitor (D2) that block PELP1 interactions with AR.[58] Since PELP1 interacts with histone modifications and epigenetic enzymes, drugs targeting epigenetic modifier enzymes may be useful in targeting PELP1 deregulated tumors.[24][25][26][57]

Notes

References

  1. ↑ "Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR". Nuclear Receptor Signaling 5: e004. 2007. doi:10.1621/nrs.05004. PMID 17525794. 
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 "The transcriptional corepressor, PELP1, recruits HDAC2 and masks histones using two separate domains". The Journal of Biological Chemistry 279 (49): 50930–41. December 2004. doi:10.1074/jbc.M406831200. PMID 15456770. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 3.5 "Molecular cloning and characterization of PELP1, a novel human coregulator of estrogen receptor alpha". The Journal of Biological Chemistry 276 (41): 38272–9. October 2001. doi:10.1074/jbc.M103783200. PMID 11481323. 
  4. ↑ 4.0 4.1 4.2 4.3 "Functional and biological properties of the nuclear receptor coregulator PELP1/MNAR". Nuclear Receptor Signaling 5: e004. 2007-01-01. doi:10.1621/nrs.05004. PMID 17525794. 
  5. ↑ 5.0 5.1 5.2 "Minireview: Deciphering the Cellular Functions of PELP1". Molecular Endocrinology 29 (9): 1222–9. September 2015. doi:10.1210/me.2015-1049. PMID 26158753. 
  6. ↑ 6.0 6.1 "PELP1--a novel estrogen receptor-interacting protein". Molecular and Cellular Endocrinology 290 (1–2): 2–7. August 2008. doi:10.1016/j.mce.2008.04.019. PMID 18571832. 
  7. ↑ 7.0 7.1 "PELP1: a review of PELP1 interactions, signaling, and biology". Molecular and Cellular Endocrinology 382 (1): 642–51. Jan 2014. doi:10.1016/j.mce.2013.07.031. PMID 23933151. 
  8. ↑ "PELP1: A novel therapeutic target for hormonal cancers". IUBMB Life 62 (3): 162–9. March 2010. doi:10.1002/iub.287. PMID 20014005. 
  9. ↑ 9.0 9.1 9.2 "The social network of PELP1 and its implications in breast and prostate cancers". Endocrine-Related Cancer 21 (4): T79–86. August 2014. doi:10.1530/ERC-13-0502. PMID 24859989. 
  10. ↑ 10.0 10.1 "Cloning, expression, and localization of MNAR/PELP1 in rodent brain: colocalization in estrogen receptor-alpha- but not in gonadotropin-releasing hormone-positive neurons". Endocrinology 146 (12): 5215–27. December 2005. doi:10.1210/en.2005-0276. PMID 16141397. 
  11. ↑ "Developmental expression of MNAR mRNA in the mouse brain". Cell and Tissue Research 320 (3): 545–9. June 2005. doi:10.1007/s00441-005-1090-z. PMID 15846512. 
  12. ↑ "Characterization of MNAR expression". Steroids 71 (4): 317–22. April 2006. doi:10.1016/j.steroids.2005.09.016. PMID 16297421. 
  13. ↑ 13.0 13.1 "Functional interactions between the estrogen receptor coactivator PELP1/MNAR and retinoblastoma protein". The Journal of Biological Chemistry 278 (24): 22119–27. June 2003. doi:10.1074/jbc.M212822200. PMID 12682072. 
  14. ↑ 14.0 14.1 "Deregulation of estrogen receptor coactivator proline-, glutamic acid-, and leucine-rich protein-1/modulator of nongenomic activity of estrogen receptor in human endometrial tumors". The Journal of Clinical Endocrinology and Metabolism 89 (12): 6130–8. December 2004. doi:10.1210/jc.2004-0909. PMID 15579769. 
  15. ↑ "Modulation of in situ estrogen synthesis by proline-, glutamic acid-, and leucine-rich protein-1: potential estrogen receptor autocrine signaling loop in breast cancer cells". Molecular Endocrinology 22 (3): 649–64. March 2008. doi:10.1210/me.2007-0350. PMID 18079323. 
  16. ↑ "Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes". Oncogene 34 (4): 506–15. Jan 2015. doi:10.1038/onc.2013.579. PMID 24469035. 
  17. ↑ "MNAR functionally interacts with both NH2- and COOH-terminal GR domains to modulate transactivation". American Journal of Physiology. Endocrinology and Metabolism 295 (5): E1047–55. November 2008. doi:10.1152/ajpendo.90429.2008. PMID 18682536. 
  18. ↑ 18.0 18.1 "Central role for PELP1 in nonandrogenic activation of the androgen receptor in prostate cancer". Molecular Endocrinology 26 (4): 550–61. April 2012. doi:10.1210/me.2011-1101. PMID 22403175. 
  19. ↑ 19.0 19.1 19.2 "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". Molecular Endocrinology 21 (3): 613–24. March 2007. doi:10.1210/me.2006-0269. PMID 17192406. 
  20. ↑ "9-cis-retinoic acid up-regulates expression of transcriptional coregulator PELP1, a novel coactivator of the retinoid X receptor alpha pathway". The Journal of Biological Chemistry 281 (22): 15394–404. June 2006. doi:10.1074/jbc.M601593200. PMID 16574651. 
  21. ↑ 21.0 21.1 "Proline-, glutamic acid-, and leucine-rich protein-1 is essential in growth factor regulation of signal transducers and activators of transcription 3 activation". Cancer Research 65 (13): 5571–7. July 2005. doi:10.1158/0008-5472.CAN-04-4664. PMID 15994929. 
  22. ↑ 22.0 22.1 "Potential role of a novel transcriptional coactivator PELP1 in histone H1 displacement in cancer cells". Cancer Research 64 (18): 6416–23. September 2004. doi:10.1158/0008-5472.CAN-04-1786. PMID 15374949. 
  23. ↑ "NXP-2 association with SUMO-2 depends on lysines required for transcriptional repression". Proceedings of the National Academy of Sciences of the United States of America 103 (14): 5308–13. April 2006. doi:10.1073/pnas.0601066103. PMID 16567619. Bibcode: 2006PNAS..103.5308R. 
  24. ↑ 24.0 24.1 24.2 "PELP1 is a reader of histone H3 methylation that facilitates oestrogen receptor-alpha target gene activation by regulating lysine demethylase 1 specificity". EMBO Reports 11 (6): 438–44. June 2010. doi:10.1038/embor.2010.62. PMID 20448663. 
  25. ↑ 25.0 25.1 25.2 25.3 "PELP1 oncogenic functions involve alternative splicing via PRMT6". Molecular Oncology 8 (2): 389–400. March 2014. doi:10.1016/j.molonc.2013.12.012. PMID 24447537. 
  26. ↑ 26.0 26.1 26.2 "PELP1 oncogenic functions involve CARM1 regulation". Carcinogenesis 34 (7): 1468–75. July 2013. doi:10.1093/carcin/bgt091. PMID 23486015. 
  27. ↑ 27.0 27.1 27.2 "Novel role of PELP1 in regulating chemotherapy response in mutant p53-expressing triple negative breast cancer cells". Breast Cancer Research and Treatment 150 (3): 487–99. April 2015. doi:10.1007/s10549-015-3339-x. PMID 25788226. 
  28. ↑ 28.0 28.1 28.2 "Proline, glutamic acid and leucine-rich protein-1 is essential for optimal p53-mediated DNA damage response". Cell Death and Differentiation 21 (9): 1409–18. September 2014. doi:10.1038/cdd.2014.55. PMID 24786831. 
  29. ↑ 29.0 29.1 29.2 "Functional implications of altered subcellular localization of PELP1 in breast cancer cells". Cancer Research 65 (17): 7724–32. September 2005. doi:10.1158/0008-5472.CAN-05-0614. PMID 16140940. 
  30. ↑ "Growth factor regulation of estrogen receptor coregulator PELP1 functions via Protein Kinase A pathway". Molecular Cancer Research 6 (5): 851–61. May 2008. doi:10.1158/1541-7786.MCR-07-2030. PMID 18505929. 
  31. ↑ 31.0 31.1 "Cyclin-dependent kinase-mediated phosphorylation plays a critical role in the oncogenic functions of PELP1". Cancer Research 70 (18): 7166–75. September 2010. doi:10.1158/0008-5472.CAN-10-0628. PMID 20807815. 
  32. ↑ 32.0 32.1 "Extranuclear functions of ER impact invasive migration and metastasis by breast cancer cells". Cancer Research 70 (10): 4092–101. May 2010. doi:10.1158/0008-5472.CAN-09-3834. PMID 20460518. 
  33. ↑ 33.0 33.1 33.2 "Therapeutic targeting of PELP1 prevents ovarian cancer growth and metastasis". Clinical Cancer Research 17 (8): 2250–9. April 2011. doi:10.1158/1078-0432.CCR-10-2718. PMID 21421858. 
  34. ↑ 34.0 34.1 34.2 "Inhibition of mTOR signaling reduces PELP1-mediated tumor growth and therapy resistance". Molecular Cancer Therapeutics 13 (6): 1578–88. June 2014. doi:10.1158/1535-7163.MCT-13-0877. PMID 24688046. 
  35. ↑ 35.0 35.1 "PELP1 overexpression in the mouse mammary gland results in the development of hyperplasia and carcinoma". Cancer Research 74 (24): 7395–405. December 2014. doi:10.1158/0008-5472.CAN-14-0993. PMID 25377474. 
  36. ↑ "Significance of PELP1/HDAC2/miR-200 regulatory network in EMT and metastasis of breast cancer". Oncogene 33 (28): 3707–16. July 2014. doi:10.1038/onc.2013.332. PMID 23975430. 
  37. ↑ "The SUMO system controls nucleolar partitioning of a novel mammalian ribosome biogenesis complex". The EMBO Journal 30 (6): 1067–78. March 2011. doi:10.1038/emboj.2011.33. PMID 21326211. 
  38. ↑ "Regulation of rDNA transcription by proto-oncogene PELP1". PLOS ONE 6 (6): e21095. 2011-01-01. doi:10.1371/journal.pone.0021095. PMID 21695158. Bibcode: 2011PLoSO...621095G. 
  39. ↑ "LAS1L interacts with the mammalian Rix1 complex to regulate ribosome biogenesis". Molecular Biology of the Cell 23 (4): 716–28. February 2012. doi:10.1091/mbc.E11-06-0530. PMID 22190735. 
  40. ↑ van Belkum, A; Boekhout, T; Bosboom, R (October 1994). "Monitoring spread of Malassezia infections in a neonatal intensive care unit by PCR-mediated genetic typing.". Journal of Clinical Microbiology 32 (10): 2528–32. doi:10.1128/JCM.32.10.2528-2532.1994. PMID 7814492. 
  41. ↑ Sareddy, GR; Zhang, Q; Wang, R; Scott, E; Zou, Y; O'Connor, JC; Chen, Y; Dong, Y et al. (1 December 2015). "Proline-, glutamic acid-, and leucine-rich protein 1 mediates estrogen rapid signaling and neuroprotection in the brain.". Proceedings of the National Academy of Sciences of the United States of America 112 (48): E6673–82. doi:10.1073/pnas.1516729112. PMID 26627258. Bibcode: 2015PNAS..112E6673S. 
  42. ↑ Thakkar, R; Wang, R; Sareddy, G; Wang, J; Thiruvaiyaru, D; Vadlamudi, R; Zhang, Q; Brann, D (2016). "NLRP3 Inflammasome Activation in the Brain after Global Cerebral Ischemia and Regulation by 17β-Estradiol.". Oxidative Medicine and Cellular Longevity 2016: 8309031. doi:10.1155/2016/8309031. PMID 27843532. 
  43. ↑ 43.0 43.1 43.2 "Oncogenic potential of the nuclear receptor coregulator proline-, glutamic acid-, leucine-rich protein 1/modulator of the nongenomic actions of the estrogen receptor". Cancer Research 67 (11): 5505–12. June 2007. doi:10.1158/0008-5472.CAN-06-3647. PMID 17545633. 
  44. ↑ "Therapeutic targeting of PELP1 prevents ovarian cancer growth and metastasis". Clinical Cancer Research 17 (8): 2250–9. April 2011. doi:10.1158/1078-0432.CCR-10-2718. PMID 21421858. 
  45. ↑ "Significance of PELP1 in ER-negative breast cancer metastasis". Molecular Cancer Research 10 (1): 25–33. Jan 2012. doi:10.1158/1541-7786.MCR-11-0456. PMID 22086908. 
  46. ↑ "Prognostic significance of proline, glutamic acid, leucine rich protein 1 (PELP1) in triple-negative breast cancer: a retrospective study on 129 cases". BMC Cancer 15: 699. 2015-01-01. doi:10.1186/s12885-015-1694-y. PMID 26472563. 
  47. ↑ "Novel estrogen receptor coactivator PELP1/MNAR gene and ERbeta expression in salivary duct adenocarcinoma: potential therapeutic targets". Human Pathology 36 (6): 670–5. June 2005. doi:10.1016/j.humpath.2005.03.016. PMID 16021574. 
  48. ↑ "Increased expression of proline-, glutamic acid- and leucine-rich protein PELP1 in non-small cell lung cancer". Biomedicine & Pharmacotherapy 73: 97–101. July 2015. doi:10.1016/j.biopha.2015.05.015. PMID 26211588. 
  49. ↑ "Involvement of the tubulin tyrosine ligase-like family member 4 polyglutamylase in PELP1 polyglutamylation and chromatin remodeling in pancreatic cancer cells". Cancer Research 70 (10): 4024–33. May 2010. doi:10.1158/0008-5472.CAN-09-4444. PMID 20442285. 
  50. ↑ "PELP1 suppression inhibits colorectal cancer through c-Src downregulation". Oxidative Medicine and Cellular Longevity 2014: 193523. 2014-01-01. doi:10.1155/2014/193523. PMID 24967003. 
  51. ↑ 51.0 51.1 "Significance of ER-Src axis in hormonal therapy resistance". Breast Cancer Research and Treatment 130 (2): 377–85. November 2011. doi:10.1007/s10549-010-1312-2. PMID 21184269. 
  52. ↑ 52.0 52.1 "Extranuclear coactivator signaling confers insensitivity to tamoxifen". Clinical Cancer Research 15 (12): 4123–30. June 2009. doi:10.1158/1078-0432.CCR-08-2347. PMID 19470742. 
  53. ↑ "Cytoplasmic PELP1 and ERRgamma protect human mammary epithelial cells from Tam-induced cell death". PLOS ONE 10 (3): e0121206. 2015-01-01. doi:10.1371/journal.pone.0121206. PMID 25789479. Bibcode: 2015PLoSO..1021206G. 
  54. ↑ "Changes in androgen receptor nongenotropic signaling correlate with transition of LNCaP cells to androgen independence". Cancer Research 64 (19): 7156–68. October 2004. doi:10.1158/0008-5472.CAN-04-1121. PMID 15466214. 
  55. ↑ Girard, BJ; Knutson, TP; Kuker, B; McDowell, L; Schwertfeger, KL; Ostrander, JH (23 November 2016). "Cytoplasmic Localization of Proline, Glutamic Acid, Leucine Rich Protein 1 (PELP1) Induces Breast Epithelial Cell Migration through Upregulation of Inhibitor of kappa B Kinase Epsilon and Inflammatory Crosstalk with Macrophages.". The Journal of Biological Chemistry 292 (1): 339–350. doi:10.1074/jbc.M116.739847. PMID 27881676. 
  56. ↑ "The prognostic significance of PELP1 expression in invasive breast cancer with emphasis on the ER-positive luminal-like subtype". Breast Cancer Research and Treatment 120 (3): 603–12. April 2010. doi:10.1007/s10549-009-0419-9. PMID 19495959. https://hal.archives-ouvertes.fr/hal-00535368/file/PEER_stage2_10.1007%252Fs10549-009-0419-9.pdf. 
  57. ↑ 57.0 57.1 "Targeting the PELP1-KDM1 axis as a potential therapeutic strategy for breast cancer". Breast Cancer Research 14 (4): R108. 2012-01-01. doi:10.1186/bcr3229. PMID 22812534. 
  58. ↑ "Peptidomimetic targeting of critical androgen receptor-coregulator interactions in prostate cancer". Nature Communications 4: 1923. 2013-01-01. doi:10.1038/ncomms2912. PMID 23715282. Bibcode: 2013NatCo...4.1923R. 

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