Reference - Detail
| RRC ID | 40004 |
|---|---|
| Author | Walker MP, Stopford CM, Cederlund M, Fang F, Jahn C, Rabinowitz AD, Goldfarb D, Graham DM, Yan F, Deal AM, Fedoriw Y, Richards KL, Davis IJ, Weidinger G, Damania B, Major MB. |
| Title | FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma. |
| Journal | Sci Signal |
| Abstract |
The transcription factor FOXP1 (forkhead box protein P1) is a master regulator of stem and progenitor cell biology. In diffuse large B cell lymphoma (DLBCL), copy number amplifications and chromosomal translocations result in overexpression of FOXP1. Increased abundance of FOXP1 in DLBCL is a predictor of poor prognosis and resistance to therapy. We developed a genome-wide, mass spectrometry-coupled, gain-of-function genetic screen, which revealed that FOXP1 potentiates β-catenin-dependent, Wnt-dependent gene expression. Gain- and loss-of-function studies in cell models and zebrafish confirmed that FOXP1 was a general and conserved enhancer of Wnt signaling. In a Wnt-dependent fashion, FOXP1 formed a complex with β-catenin, TCF7L2 (transcription factor 7-like 2), and the acetyltransferase CBP [CREB (adenosine 3',5'-monophosphate response element-binding protein)-binding protein], and this complex bound the promoters of Wnt target genes. FOXP1 promoted the acetylation of β-catenin by CBP, and acetylation was required for FOXP1-mediated potentiation of β-catenin-dependent transcription. In DLBCL, we found that FOXP1 promoted sensitivity to Wnt pathway inhibitors, and knockdown of FOXP1 or blocking β-catenin transcriptional activity slowed xenograft tumor growth. These data connect excessive FOXP1 with β-catenin-dependent signal transduction and provide a molecular rationale for Wnt-directed therapy in DLBCL. |
| Volume | 8(362) |
| Pages | ra12 |
| Published | 2015-2-3 |
| DOI | 10.1126/scisignal.2005654 |
| PII | 8/362/ra12 |
| PMID | 25650440 |
| PMC | PMC4356208 |
| MeSH | Animals Enhancer Elements, Genetic Forkhead Transcription Factors / metabolism* Gene Expression Profiling Gene Expression Regulation, Neoplastic* HEK293 Cells Humans Ligands Lymphoma, Large B-Cell, Diffuse / metabolism* Mass Spectrometry Mice Mice, Inbred NOD Mice, SCID Neoplasm Transplantation Prognosis Protein Isoforms / metabolism Repressor Proteins / metabolism* Transcription Factor 7-Like 2 Protein / metabolism Wnt Proteins / metabolism* Wnt Signaling Pathway* Zebrafish beta Catenin / metabolism* |
| IF | 6.467 |
| Times Cited | 32 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 14 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Zebrafish | Tg(6xTcf/LefBS-miniP:d2EGFP)/isi04 |