| RRC ID |
40004
|
| 著者 |
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.
|
| タイトル |
FOXP1 potentiates Wnt/β-catenin signaling in diffuse large B cell lymphoma.
|
| ジャーナル |
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.
|
| 巻・号 |
8(362)
|
| ページ |
ra12
|
| 公開日 |
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
|
| 引用数 |
32
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
CELL BIOLOGY
|
| リソース情報 |
| ゼブラフィッシュ |
Tg(6xTcf/LefBS-miniP:d2EGFP)/isi04 |
