Skip to Main content Skip to Navigation
Journal articles

β-Catenin-Independent Activation of TCF1/LEF1 in Human Hematopoietic Tumor Cells through Interaction with ATF2 Transcription Factors

Abstract : The role of Wnt signaling in embryonic development and stem cell maintenance is well established and aberrations leading to the constitutive up-regulation of this pathway are frequent in several types of human cancers. Upon ligand-mediated activation, Wnt receptors promote the stabilization of b-catenin, which translocates to the nucleus and binds to the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of transcription factors to regulate the expression of Wnt target genes. When not bound to b-catenin, the TCF/LEF proteins are believed to act as transcriptional repressors. Using a specific lentiviral reporter, we identified hematopoietic tumor cells displaying constitutive TCF/LEF transcriptional activation in the absence of b-catenin stabilization. Suppression of TCF/LEF activity in these cells mediated by an inducible dominant-negative TCF4 (DN-TCF4) inhibited both cell growth and the expression of Wnt target genes. Further, expression of TCF1 and LEF1, but not TCF4, stimulated TCF/LEF reporter activity in certain human cell lines independently of b-catenin. By a complementary approach in vivo, TCF1 mutants, which lacked the ability to bind to b-catenin, induced Xenopus embryo axis duplication, a hallmark of Wnt activation, and the expression of the Wnt target gene Xnr3. Through generation of different TCF1-TCF4 fusion proteins, we identified three distinct TCF1 domains that participate in the b-catenin-independent activity of this transcription factor. TCF1 and LEF1 physically interacted and functionally synergized with members of the activating transcription factor 2 (ATF2) family of transcription factors. Moreover, knockdown of ATF2 expression in lymphoma cells phenocopied the inhibitory effects of DN-TCF4 on the expression of target genes associated with the Wnt pathway and on cell growth. Together, our findings indicate that, through interaction with ATF2 factors, TCF1/LEF1 promote the growth of hematopoietic malignancies in the absence of b-catenin stabilization, thus establishing a new mechanism for TCF1/LEF1 transcriptional activity distinct from that associated with canonical Wnt signaling.
Document type :
Journal articles
Complete list of metadatas

Cited literature [73 references]  Display  Hide  Download

https://hal-normandie-univ.archives-ouvertes.fr/hal-02017513
Contributor : Luca Grumolato <>
Submitted on : Wednesday, February 13, 2019 - 11:13:38 AM
Last modification on : Tuesday, April 7, 2020 - 3:36:04 PM
Long-term archiving on: : Tuesday, May 14, 2019 - 6:44:11 PM

File

Grumolato_PLoSGenetics2013.pdf
Publisher files allowed on an open archive

Identifiers

Collections

Citation

Luca Grumolato, Guizhong Liu, Tomomi Haremaki, Sathish Mungamuri, Phyllus Mong, et al.. β-Catenin-Independent Activation of TCF1/LEF1 in Human Hematopoietic Tumor Cells through Interaction with ATF2 Transcription Factors. PLoS Genetics, Public Library of Science, 2013, 9 (8), pp.e1003603. ⟨10.1371/journal.pgen.1003603⟩. ⟨hal-02017513⟩

Share

Metrics

Record views

62

Files downloads

89