Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family–mediated transcriptional activation of TGFβ2

Zhou, Wenlai; Lin, Lizhu; Majumdar, Årindam; Li, Xue; Zhang, Xiaoxue; Liu, Wei; Etheridge, Leah; Shi, Yunqing; Martin, James F.; Ven, Willem Van de; Kaartinen, Vesa; Wynshaw‐Boris, Anthony; McMahon, Andrew P.; Rosenfeld, Michael G.; Evans, Sylvia M.

doi:10.1038/ng2112

Cited by 170 publications

(169 citation statements)

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“…In our study, ERG-induced morphological shape changes also complement the initial global ChIP-chip analysis that determined cell adhesion as a significantly enriched biological theme (Table 2). Moreover, there is surmounting evidence of WNT11 as a morphogenic and cytoskeletal effector molecule (Zhou et al, 2007;Flaherty and Dawn, 2008;Lai et al, 2009;Uysal-onganer et al, 2010). Morphological transformation involving ERG gene activation of WNT11 may have a role in the bone marrow microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

et al. 2011

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E26 transforming sequence-related gene (ERG) is a transcription factor involved in normal hematopoiesis and is dysregulated in leukemia. ERG mRNA overexpression was associated with poor prognosis in a subset of patients with T-cell acute lymphoblastic leukemia (T-ALL) and acute myeloid leukemia (AML). Herein, a genome-wide screen of ERG target genes was conducted by chromatin immunoprecipitation-on-chip (ChIP-chip) in Jurkat cells. In this screen, 342 significant annotated genes were derived from this global approach. Notably, ERG-enriched targets included WNT signaling genes: WNT11, WNT2, WNT9A, CCND1 and FZD7. Furthermore, chromatin immunoprecipitation (ChIP) of normal and primary leukemia bone marrow material also confirmed WNT11 as a target of ERG in six of seven patient samples. A larger sampling of patient diagnostic material revealed that ERG and WNT11 mRNA were coexpressed in 80% of AML (n ¼ 30) and 40% in T-ALL (n ¼ 30) bone marrow samples. Small interfering RNA (siRNA)-mediated knockdown of ERG confirmed downregulation of WNT11 transcripts. Conversely, in a tet-on ERG-inducible assay, WNT11 transcripts were costimulated. A WNT pathway agonist, 6-bromoindirubin-3-oxime (BIO), was used to determine the effect of cell growth on the ERG-inducible cells. The addition of BIO resulted in an ERG-dependent proliferative growth advantage over ERG-uninduced cells. Finally, ERG induction prompted morphological transformation whereby round unpolarized K562 cells developed elongated protrusions and became polarized. This morphological transformation could effectively be inhibited with BIO and with siRNA knockdown of WNT11. In conclusion, ERG transcriptional networks in leukemia converge on WNT signaling targets. Specifically, WNT11 emerged as a direct target of ERG. Potent ERG induction promoted morphological transformation through WNT11 signals. The findings in this study unravel new ERG-directed molecular signals that may contribute to the resistance of current therapies in acute leukemia patients with poor prognosis characterized by high ERG mRNA expression.

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Section: Discussionmentioning

confidence: 99%

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

et al. 2011

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“…92 Wnt11 has been shown to regulate N-cadherin expression in the quail mesodermal progenitor cell line QCE6, 59 and N-cadherin expression and function in neonatal rat cardiomyocytes is regulated by Wnt/Fz2 signaling. 93 Wnt11 knockout embryos display defects in the OFT (see below) 77 but also thinner ventricular walls and less trabeculae. A detailed analysis indicated defects in N-cadherin/␤-catenin mediated cell adhesion as well.…”

Section: From the Tubular Heart Tube To The Four Chambers Wnt Signalimentioning

confidence: 99%

“…74,75 This putative functional redundancy might explain why a loss of Wnt11 results in an early cardiac phenotype in Xenopus 49,51 but not in the mouse with later phenotypes. 76,77 Slightly later, however, it might be Wnt2b that regulates proliferation of the common cardiac progenitor through a Wnt/␤-catenin pathway. 78 enter the heart tube either from the anterior site giving rise to the right ventricle and the OFT or they can enter from the posterior site contributing to the atria and the inflow tract region.…”

Section: Cardiac Specification: Positive Influence Of Noncanonical Wnmentioning

confidence: 99%

“…109 Wnt11 is another Wnt ligand expressed in the OFT and activates a noncanonical Wnt pathway regulating the expression of TGF␤2. 77 Furthermore, Wnt5a and Wnt11 are required for cytoskeletal rearrangements during morphogenesis of the OFT. Others could show a requirement for components of the planar cell polarity (PCP) pathway in OFT formation.…”

Section: Septation and Cardiac Valve Formationmentioning

confidence: 99%

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The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development

Gessert

Kühl

2010

Circulation Research

358

310

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Understanding heart development on a molecular level is a prerequisite for uncovering the causes of congenital heart diseases. Therapeutic approaches that try to enhance cardiac regeneration or that involve the differentiation of resident cardiac progenitor cells or patient-specific induced pluripotent stem cells will also benefit tremendously from this knowledge. Wnt proteins have been shown to play multiple roles during cardiac differentiation and development. They are extracellular growth factors that activate different intracellular signaling branches. Here, we summarize our current understanding of how these factors affect different aspects of cardiogenesis, starting from early specification of cardiac progenitors and continuing on to later developmental steps, such as morphogenetic processes, valve formation, and establishment of the conduction system. (Circ Res. 2010;107:186-199.)

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“…The TGFB 2 promoter constructs comprise a genomic DNA fragment spanning bases −77 to +63 of TGF b 2 (relative to the transcriptional start codon) cloned into pGL3-basic vector with or without a CREB1-binding site mutation (CGTCAC to TGGCAC; ref. 38 ).…”

Section: Plasmidsmentioning

confidence: 99%

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

Rodón¹,

Gonzàlez-Juncà²,

Inda³

et al. 2014

Cancer Discovery

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In advanced cancer, including glioblastoma, the TGFβ pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGFβ activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGFβ can induce TGFβ2, generating an autocrine loop leading to aberrantly high levels of TGFβ2. We identifi ed cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGFβ2 by TGFβ. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGFβ to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGFβ2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGFβ2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGFβ2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGFβ treatments and a therapeutic target in glioblastoma. SIGNIFICANCE:TGFβ is considered a promising therapeutic target, and several clinical trials using TGFβ inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGFβ2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGFβ therapies. Cancer Discov; 4(10); 1230-41.

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Modulation of morphogenesis by noncanonical Wnt signaling requires ATF/CREB family–mediated transcriptional activation of TGFβ2

Cited by 170 publications

References 50 publications

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

Genome-wide screen reveals WNT11, a non-canonical WNT gene, as a direct target of ETS transcription factor ERG

The Multiple Phases and Faces of Wnt Signaling During Cardiac Differentiation and Development

Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma

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