title: 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 β-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 β-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 β-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 β-catenin. By a complementary approach in vivo, TCF1 mutants, which lacked the ability to bind to β-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 β-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 β-catenin stabilization, thus establishing a new mechanism for TCF1/LEF1 transcriptional activity distinct from that associated with canonical Wnt signaling.
authors: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.
authors: Luca
authors: L
authors: Grumolato
authors: Guizhong
authors: G
authors: Liu
authors: Tomomi
authors: T
authors: Haremaki
authors: Sathish Kumar
authors: SK
authors: Mungamuri
authors: Phyllus
authors: P
authors: Mong
authors: Gal
authors: G
authors: Akiri
authors: Pablo
authors: P
authors: Lopez-Bergami
authors: Adriana
authors: A
authors: Arita
authors: Youssef
authors: Y
authors: Anouar
authors: Marek
authors: M
authors: Mlodzik
authors: Ze'ev A
authors: ZA
authors: Ronai
authors: Joshua
authors: J
authors: Brody
authors: Daniel C
authors: DC
authors: Weinstein
authors: Stuart A
authors: SA
authors: Aaronson
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D018507:Gene Expression Regulation, Developmental; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D015533:Transcriptional Activation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics; D014982:Xenopus laevis; D051176:beta Catenin / Q000235:genetics*
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051176:beta Catenin
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