PELP-1

Mammalian protein found in Homo sapiens

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. is a transcriptional corepressor for nuclear receptors such as glucocorticoid receptors and a coactivator for estrogen receptors. Proline , glutamic acid , and leucine rich protein 1 (PELP1) is transcription coregulator and modulates functions of several hormonal receptors and transcription factors. PELP1 plays essential roles in hormonal signaling, cell cycle progression, and ribosomal biogenesis. 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.

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. Currently, there are two known isoforms (long 3.8 Kb and short 3.4 Kb) and short isoform is widely expressed in cancer cells.

The PELP1 protein encodes a protein of 1130 amino acids, and exhibits both cytoplasmic and nuclear localization depending on the tissue. ERR alpha, PR, GR, AR, and RXR. PELP1 also functions as a coregulator of several other transcription factors, including AP1, SP1, NFkB, and FHL2. SUMO2, lysine specific demethylase 1 (KDM1), PRMT6, and CARM1. PELP1 also interacts with cell cycle regulators such as pRb. and p53. PELP1 is phosphorylated by hormonal and growth factor signals. PELP1 phosphorylation status is also influenced by cell cycle progression, and it is a substrate of CDKs. Further, PELP1 is phosphorylated by DNA damage induced kinases (ATM, ATR, DNA PKcs). PI3K STAT3 PELP1 participates in E2 mediated cell proliferation and is a substrate of CDK4/cyclin D1, CDK2/cyclin E and CDK2/cyclin A complexes. 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. PELP1 is needed for optimal DNA damage response, is phosphorylated by DDR kinases and is important for p53 coactivation function. 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. 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. 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. PELP1 is a proto oncogene that provides cancer cells with a distinct growth and survival advantage. PELP1 deregulation in vivo promotes development of mammary gland hyperplasia and carcinoma endometrial, prostate, pancreas, and colon neoplasms. PELP1 signaling contributes to hormonal therapy resistance. Altered localization of PLP1 contributes to tamoxifen resistance via excessive activation of the AKT pathway and cytoplasmic PELP1 induces signaling pathways that converge on ERRγ to promote cell survival in the presence of tamoxifen. AR, PELP1 and Src form constitutive complexes in prostate neoplasms model cells that exhibit androgen independence. 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.

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. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen 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. Since PELP1 interacts with histone modifications and epigenetic enzymes, drugs targeting epigenetic modifier enzymes may be useful in targeting PELP1 deregulated tumors.