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更新于：2024-09-19

PHF1

更新于：2024-09-19

基本信息

别名

hPCl1、hPHF1、MTF2L2

+ [6]

简介

Polycomb group (PcG) that specifically binds histone H3 trimethylated at 'Lys-36' (H3K36me3) and recruits the PRC2 complex. Involved in DNA damage response and is recruited at double-strand breaks (DSBs). Acts by binding to H3K36me3, a mark for transcriptional activation, and recruiting the PRC2 complex: it is however unclear whether recruitment of the PRC2 complex to H3K36me3 leads to enhance or inhibit H3K27me3 methylation mediated by the PRC2 complex. According to some reports, PRC2 recruitment by PHF1 promotes H3K27me3 and subsequent gene silencing by inducing spreading of PRC2 and H3K27me3 into H3K36me3 loci (PubMed:18285464, PubMed:23273982). According to another report, PHF1 recruits the PRC2 complex at double-strand breaks (DSBs) and inhibits the activity of PRC2 (PubMed:23142980). Regulates p53/TP53 stability and prolonges its turnover: may act by specifically binding to a methylated from of p53/TP53.

关联

项与 PHF1 相关的药物

UNC-6641

靶点

PHF1

作用机制

PHF1 inhibitors

在研机构

The University of North Carolina at Chapel Hill

原研机构

The University of North Carolina at Chapel Hill

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 PHF1 相关的临床结果

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100 项与 PHF1 相关的转化医学

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0 项与 PHF1 相关的专利（医药）

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368

项与 PHF1 相关的文献（医药）

2024-07-01·Alzheimer's & Dementia

Inpp5d haplodeficiency alleviates tau pathology in the PS19 mouse model of Tauopathy

Article

作者: Oblak, Adrian L ; Lee-Gosselin, Audrey ; Mason, Emily ; Lamb, Bruce T ; Lloyd, Christopher D ; Moutinho, Miguel ; Chu, Shaoyou ; Perkins, Abigail ; Soni, Disha M ; Ingraham, Cynthia M ; Lin, Peter Bor-Chian

AbstractINTRODUCTIONA noncoding variant (rs35349669) within

INPP5D

, a lipid and protein phosphatase restricted to microglia in the brain, is linked to increased susceptibility to Alzheimer's disease (AD). While Inpp5d is well‐studied in amyloid pathology, its role in tau pathology remains unclear.METHODSPS19 Tauopathy mice were crossed with Inpp5d‐haplodeficient (Inpp5d+/−) mice to examine the impact of Inpp5d in tau pathology.RESULTSIncreased INPP5D expression correlated positively with phospho‐Tau AT8 in PS19 mice. Inpp5d haplodeficiency mitigated hyperphosphorylated tau levels (AT8, AT180, AT100, and PHF1) and motor deficits in PS19 mice. Transcriptomic analysis revealed an up‐regulation of genes associated with immune response and cell migration.DISCUSSIONOur findings define an association between INPP5D expression and tau pathology in PS19 mice. Alleviation in hyperphosphorylated tau, motor deficits, and transcriptomics changes in haplodeficient‐Inpp5d PS19 mice indicate that modulation in INPP5D expression may provide therapeutic potential for mitigating tau pathology and improving motor deficits.Highlights

The impact of Inpp5d in the context of tau pathology was studied in the PS19 mouse model.

INPP5D expression is associated with tau pathology.

Reduced Inpp5d expression in PS19 mice improved motor functions and decreased total and phospho‐Tau levels.

Inpp5d haplodeficiency in PS19 mice modulates gene expression patterns linked to immune response and cell migration.

These data suggest that inhibition of Inpp5d may be a therapeutic approach in tauopathies.

2024-06-27·Cureus

Ossifying Fibromyxoid Tumor of the Shoulder: A Case Report

Article

作者: Muralidhar, Rohit ; Yousaf, Abdullah ; Castilla, Maria ; Nash, Joel D

Ossifying fibromyxoid tumor (OFMT) is a rare, slow-growing, mesenchymal tumor with intermediate malignant potential, predominantly affecting middle-aged individuals. Histologically, it presents as a fibrous capsule or pseudocapsule, with a complete or incomplete lamellar bone shell surrounding oval/polygonal cells within a fibromyxoid matrix. Advances in immunohistochemistry have facilitated OFMT identification, with S100 protein expression and INI-1 loss being notable features. CD10 expression is also reported in a small minority of cases. Recent studies highlight a translocation of the PHF-1 gene, proposing a possible etiology for tumorigenesis. Treatment involves wide excision, with long-term follow-up for recurrence or metastasis. In this case, a 61-year-old White male presented to the outpatient surgical office with a painless mass on his right shoulder. The patient reported that the mass first appeared three to four years prior and that it had been growing slowly since the initial presentation. On examination, the patient had a well-circumscribed, 1.5 x 1.5 cm, soft, nontender, nonmobile subcutaneous mass on his right shoulder. The mass was initially suspected to be a subcutaneous cyst based on physical exam, but surgical excision and histopathology established the diagnosis of OFMT that extended to the margins of the specimen. The patient underwent a wider excision for margins and has had a benign postoperative course. The patient was referred to dermatology and oncology for continuation of care. This case demonstrates the necessity for a thorough work-up, appropriate excision, and histopathologic examination to rule in diagnoses of lower incidence with the potential for a worse prognosis. Appropriate and timely diagnoses can guide proper screening for cancer recurrence and management.

2024-03-05·Proceedings of the National Academy of Sciences1区 · 综合性期刊

Structures of AT8 and PHF1 phosphomimetic tau: Insights into the posttranslational modification code of tau aggregation

1区 · 综合性期刊

Article

作者: Duan, Pu ; Mammeri, Nadia El ; Hong, Mei ; Dregni, Aurelio J.

The microtubule-associated protein tau aggregates into amyloid fibrils in Alzheimer’s disease and other neurodegenerative diseases. In these tauopathies, tau is hyperphosphorylated, suggesting that this posttranslational modification (PTM) may induce tau aggregation. Tau is also phosphorylated in normal developing brains. To investigate how tau phosphorylation induces amyloid fibrils, here we report the atomic structures of two phosphomimetic full-length tau fibrils assembled without anionic cofactors. We mutated key Ser and Thr residues to Glu in two regions of the protein. One construct contains three Glu mutations at the epitope of the anti-phospho-tau antibody AT8 (AT8-3E tau), whereas the other construct contains four Glu mutations at the epitope of the antibody PHF1 (PHF1-4E tau). Solid-state NMR data show that both phosphomimetic tau mutants form homogeneous fibrils with a single set of chemical shifts. The AT8-3E tau rigid core extends from the R3 repeat to the C terminus, whereas the PHF1-4E tau rigid core spans R2, R3, and R4 repeats. Cryoelectron microscopy data show that AT8-3E tau forms a triangular multi-layered core, whereas PHF1-4E tau forms a triple-stranded core. Interestingly, a construct combining all seven Glu mutations exhibits the same conformation as PHF1-4E tau. Scalar-coupled NMR data additionally reveal the dynamics and shape of the fuzzy coat surrounding the rigid cores. These results demonstrate that specific PTMs induce structurally specific tau aggregates, and the phosphorylation code of tau contains redundancy.