PELP-1
PELP1 | |||
---|---|---|---|
Identifiers | |||
Gene ontology | |||
Molecular function | |||
Cellular component | |||
Biological process | |||
Sources:Amigo / QuickGO |
Ensembl | |||||||||
---|---|---|---|---|---|---|---|---|---|
UniProt | |||||||||
RefSeq (mRNA) | |||||||||
RefSeq (protein) | |||||||||
Location (UCSC) | Chr 17: 4.67 – 4.7 Mb | Chr 11: 70.28 – 70.3 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
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
Proline-, glutamic acid-, and leucine-rich protein 1 (PELP1) is
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.[7][14][15][16] Currently, there are two known isoforms (long 3.8 Kb and short 3.4 Kb) and short isoform is widely expressed in cancer cells.[17]
Structure
The PELP1 protein encodes a protein of 1130 amino acids, and exhibits both cytoplasmic and nuclear localization depending on the tissue.
PELP1 has a histone binding domain and interacts with chromatin-modifying complexes, including
PELP1 is
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.[8][9][11] PELP1 participates in activation of ESR1 extra-nuclear actions[8][33] by coupling ESR1 with Src kinase[36] PI3K[37] STAT3 [25] ILK1 [36] and mTOR[38] PELP1 participates in E2-mediated cell proliferation and is a substrate of CDK4/cyclin D1, CDK2/cyclin E and CDK2/cyclin A complexes.[35] Studies using TG mice model suggested the existence of an autocrine loop involving the CDK–cyclin D1–PELP1 axis in promoting mammary tumorigenesis [39]
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.[6][26][28][29][30] 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.[40] PELP1 is needed for optimal DNA damage response, is phosphorylated by DDR kinases and is important for p53 coactivation function.[32] PELP1 also interacts with MTp53, regulates its recruitment, and alters MTp53 target gene expression. PELP1 depletion contributes to increased stability of E2F1.[31] 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.[29]
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.[41][42][43] 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.[44]
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.[10][14] PELP1 plays an essential role in E2-mediated rapid extranuclear signaling, neuroprotection, and cognitive function in the brain.[45] 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.[46]
PELP1 is a proto-oncogene[47] that provides cancer cells with a distinct growth and survival advantage.[9][13] PELP1 interacts with various enzymes that modulate the cytoskeleton, cell migration, and metastasis.[47][48][49] PELP1 deregulation in vivo promotes development of mammary gland hyperplasia and carcinoma [39] PELP1 is implicated in progression of breast,[31][38][47][50] endometrial,[18] ovarian,[37] salivary[51] prostate,[22][23] lung,[52] pancreas,[53] and colon[54] neoplasms.
PELP1 signaling contributes to hormonal therapy resistance.[8][13][55] Altered localization of PLP1 contributes to tamoxifen resistance via excessive activation of the AKT pathway [33][56] and cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of tamoxifen.[57] AR, PELP1 and Src form constitutive complexes in prostate neoplasms model cells that exhibit androgen independence.[58] 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.[59]
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.[60] Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen [56] and PELP1 deregulated tumors respond to Src kinase[55] and mTOR inhibitors.[38] Treatment of breast and ovarian cancer xenografts with liposomal PELP1–siRNA–DOPC formulations revealed that knockdown of PELP1 significantly reduce the tumor growth.[37][61] 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.[62] Since PELP1 interacts with histone modifications and epigenetic enzymes, drugs targeting epigenetic modifier enzymes may be useful in targeting PELP1 deregulated tumors.[28][29][30][61]
Notes
Wikidata Q36818434 . |
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000141456 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000018921 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- PMID 17525794.
- ^ S2CID 8317620.
- ^ PMID 11481323.
- ^ PMID 17525794.
- ^ PMID 26158753.
- ^ PMID 18571832.
- ^ PMID 23933151.
- PMID 20014005.
- ^ PMID 24859989.
- ^ PMID 16141397.
- S2CID 20181223.
- S2CID 23777236.
- ^ PMID 12682072.
- ^ PMID 15579769.
- PMID 18079323.
- PMID 24469035.
- PMID 18682536.
- ^ PMID 22403175.
- ^ PMID 17192406.
- S2CID 21854752.
- ^ PMID 15994929.
- ^ S2CID 16994746.
- PMID 16567619.
- ^ PMID 20448663.
- ^ PMID 24447537.
- ^ PMID 23486015.
- ^ PMID 25788226.
- ^ PMID 24786831.
- ^ PMID 16140940.
- PMID 18505929.
- ^ PMID 20807815.
- ^ PMID 20460518.
- ^ PMID 21421858.
- ^ PMID 24688046.
- ^ PMID 25377474.
- PMID 23975430.
- PMID 21326211.
- PMID 21695158.
- PMID 22190735.
- PMID 7814492.
- PMID 26627258.
- PMID 27843532.
- ^ PMID 17545633.
- PMID 21421858.
- PMID 22086908.
- PMID 26472563.
- PMID 16021574.
- PMID 26211588.
- PMID 20442285.
- PMID 24967003.
- ^ PMID 21184269.
- ^ PMID 19470742.
- PMID 25789479.
- S2CID 9228479.
- PMID 27881676.
- S2CID 34913351.
- ^ PMID 22812534.
- PMID 23715282.
External links
- PELP1 protein, human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- .