Peptidylprolyl Isomerase Pin1 Directly Enhances the DNA Binding Functions of Estrogen Receptor α

Rajbhandari, Prashant; Ozers, Mary Szatkowski; Solodin, Natalia; Warren, Christopher L.; Alarid, Elaine T.

doi:10.1074/jbc.m114.621698

Cited by 17 publications

(21 citation statements)

References 87 publications

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“…Pin1 has been reported to directly enhance the DNA binding functions of oestrogen receptor α (ERα). Pin1 selectively enhances the binding affinity of ER to consensus DNA elements that Pin1 isomerization of phosphorylated ERα directly regulates the function of the adjacent DNA binding domain, and this interaction is further modulated by ligand binding in the ligand‐binding domain 39 . Our study identified two binding sites of Pin1 and p65 in the IL‐18 promoter and confirmed that the two molecules simultaneously bind to the promoter region and enhance transcription.…”

Section: Discussionsupporting

confidence: 69%

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF‐κB‐IL‐18 feedback loop

et al. 2020

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Objectives: Accumulated evidence suggests that Pin1 contributes to oncogenesis of diverse cancers. However, the underlying mechanism of oncogenic function of Pin1 in PDAC requires further exploration. Materials and Methods: IHC was performed using PDAC tissues. Western blot, PCR, immunofluorescence and transwell were performed using cell lines. GSEA were applied for possible downstream pathways. ChIP assay and dual luciferase were used for assessment of transcriptional activity. Results: Both Pin1 and IL-18 levels are increased in primary PDAC tissues and that their levels are positively correlated. High expression of IL-18 is a predictor of poor prognoses. Pin1 promoted pancreatic cancer cell proliferation and motility by increasing IL-18 expression, while Pin1 knockdown also inhibited the tumour-promoting effect of IL-18. Both Pin1 and IL-18 could enhance the NFκB activity in pancreatic cancer cells. When bound to the p65 protein, Pin1 promoted p65 phosphorylation and its nuclear translocation. In the nucleus, Pin1 and p65 simultaneously bound to the IL-18 promoter and enhanced IL-18 transcription. In addition, recruitment of p65 to the IL-18 promoter was decreased in Pin1-silenced cells. Conclusions: Our study improves the understanding of Pin1 in tumour-promoting inflammation in PDAC, which is a hallmark of cancer; Pin1 interacted with p65 in PDAC and enhanced NF-κB signalling and downstream transcriptional activation of IL-18, with increased IL-18 continuously activating NF-κB signalling, which then forms a positive feedback loop.

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Section: Discussionsupporting

confidence: 69%

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF‐κB‐IL‐18 feedback loop

et al. 2020

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“…Pin1 binds to the N-terminal Ser118-Pro motif in the intrinsic activation function 1 (AF1) domain of ERα (Rajbhandari et al, 2012). Binding of Pin1 and the subsequent Pin1-mediated conformational change via isomerization increases ERα DNA binding activity with a concomitant increase in ERα transcriptional activity in estrogen activated breast cancer cells (Rajbhandari et al, 2015). Pin1 also promotes the binding of c-Myc to the DNA, independent of the protein stability regulated by Pin1 (Farrell et al, 2013).…”

Section: Dna Binding and Transactivationmentioning

confidence: 99%

“…This regulation requires Pin1 PPIase activity and the phosphorylation of c-Myc on Ser62-Pro63. While Pin1 stimulates the DNA binding activity of ERa and c-Myc, but the Pin1 binding motifs on ERa or c-Myc are not within the DNA binding domain (Farrell et al, 2013;Rajbhandari et al, 2015). How Pin1-mediated isomerization in one region could affect the activity of the DNA binding domain on a different region?…”

Section: Dna Binding and Transactivationmentioning

confidence: 99%

“…For example, Pin1 regulates the nucleocytoplasmic shuttling and the stability of RelA and β-catenin (Ryo et al, 2001(Ryo et al, , 2003. Pin1 also regulates both the stability and DNA binding activity ERa (Rajbhandari et al, 2014(Rajbhandari et al, , 2015. Via these multi-level regulations, Pin1 might impose the spatiotemporal control of the expression of a subset of genes.…”

Section: Summary and Perspectivesmentioning

confidence: 99%

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Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression

Chen

2020

Front. Cell Dev. Biol.

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Pin1 is a peptidyl-prolyl cis-trans isomerase that specifically binds to a phosphorylated serine or threonine residue preceding a proline (pSer/Thr-Pro) motif and catalyzes the cis-trans isomerization of proline imidic peptide bond, resulting in conformational change of its substrates. Pin1 regulates many biological processes and is also involved in the development of human diseases, like cancer and neurological diseases. Many Pin1 substrates are transcription factors and transcription regulators, including RNA polymerase II (RNAPII) and factors associated with transcription initiation, elongation, termination and post-transcription mRNA decay. By changing the stability, subcellular localization, protein-protein or protein-DNA/RNA interactions of these transcription related proteins, Pin1 modulates the transcription of many genes related to cell proliferation, differentiation, apoptosis and immune response. Here, we will discuss how Pin regulates the properties of these transcription relevant factors for effective gene expression and how Pin1-mediated transcription contributes to the diverse pathophysiological functions of Pin1.

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“…4,5 Once activated by chemicals, including a wide spectrum of endocrine disrupting chemicals, ER can further bind specific DNA sequences as a homodimer and modulate the expression of genes. [6][7][8][9] The ligand-depend mechanism of ER is depended on its structures. In common with all members of the nuclear receptor family, ER is a multi-domain protein composed of a shared architecture.…”

Section: Introductionmentioning

confidence: 99%

Bisphenol A (BPA) binding on full‐length architectures of estrogen receptor

Liu

Ying

et al. 2018

J of Cellular Biochemistry

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Previous research has shown that the major toxicity mechanism for many environment chemicals is binding with estrogen receptor (ER) and blocking endogenous estrogen access, including bisphenol A (BPA). However, the molecular level understanding the global consequence of BPA binding on the full-length architectures of ER is largely unknown, which is a necessary stage to evaluate estrogen-like toxicity of BPA. In the present work, the consequence of BPA on full-length architectures of ER was firstly modeled based on molecular dynamics, focusing on the cross communication between multi-domains including ligand binding domain (LBD) and DNA binding domain (DBD). The study proved consequence of BPA upon full-length ER structure was dependent on long-range communications between multiple protein domains. The allosteric effects occurring in LBD units could alter dimerization formation through a crucial change in residue-residue connections, which resulted in relaxation of DBD. It indicated BPA could present consequence on the full-size receptor, not only on the separate domains, but also on the cross communication among LBD, DBD, and DNA molecules. It might provide detailed insight into the knowledge about the structural characteristics of ER and its role in gene regulation, which eventually helped us evaluate the estrogen-like toxicity upon BPA binding with full-length ER.

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Peptidylprolyl Isomerase Pin1 Directly Enhances the DNA Binding Functions of Estrogen Receptor α

Cited by 17 publications

References 87 publications

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF‐κB‐IL‐18 feedback loop

Pin1 promotes pancreatic cancer progression and metastasis by activation of NF‐κB‐IL‐18 feedback loop

Pinning Down the Transcription: A Role for Peptidyl-Prolyl cis-trans Isomerase Pin1 in Gene Expression

Bisphenol A (BPA) binding on full‐length architectures of estrogen receptor

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