The Experts below are selected from a list of 273 Experts worldwide ranked by ideXlab platform
Konrad Basler - One of the best experts on this subject based on the ideXlab platform.
-
a cytoplasmic role of wnt β catenin transcriptional cofactors bcl9 bcl9l and Pygopus in tooth enamel formation
Science Signaling, 2017Co-Authors: Claudio Cantu, Konrad Basler, George Hausmann, Pierfrancesco Pagella, Tania D Shajiei, Dario Zimmerli, Tomas Valenta, Thimios A MitsiadisAbstract:Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate with β-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind β-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. We showed that Bcl9 and Bcl9l function in the cytoplasm during tooth enamel formation in a manner that is independent of Wnt-stimulated β-catenin-dependent transcription. Bcl9, Bcl9l, and Pygo2 localized mainly to the cytoplasm of the epithelial-derived ameloblasts, the cells responsible for enamel production. In ameloblasts, Bcl9 interacted with proteins involved in enamel formation and proteins involved in exocytosis and vesicular trafficking. Conditional deletion of both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in mice produced teeth with defective enamel that was bright white and deficient in iron, which is reminiscent of human tooth enamel pathologies. Overall, our data revealed that these proteins, originally defined through their function as β-catenin transcriptional cofactors, function in odontogenesis through a previously uncharacterized cytoplasmic mechanism, revealing that they have roles beyond that of transcriptional cofactors.
-
a cytoplasmic role of wnt β catenin transcriptional cofactors bcl9 bcl9l and Pygopus in tooth enamel formation
Science Signaling, 2017Co-Authors: Claudio Cantu, Konrad Basler, George Hausmann, Pierfrancesco Pagella, Tania D Shajiei, Dario Zimmerli, Tomas Valenta, Thimios A MitsiadisAbstract:Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate wit ...
-
the phd domain is required to link drosophila Pygopus to legless beta catenin and not to histone h3
Mechanisms of Development, 2009Co-Authors: Roman Kessler, George Hausmann, Konrad BaslerAbstract:In Drosophila Pygopus (Pygo) and Legless (Lgs)/BCL9 are integral components of the nuclear Wnt/Wg signaling machine. Despite intense research, ideas that account for their mode of action remain speculative. One proposition, based on a recently discovered function of PHD fingers, is that Pygo, through its PHD, may decipher the histone code. We found that human, but not Drosophila, Pygo robustly interacts with a histone-H3 peptide methylated at lysine-4. The different binding behavior is due to a single amino acid change that appears unique to Drosophilidae Pygo proteins. Rescue experiments with predicted histone binding mutants showed that in Drosophila the ability to bind histones is not essential. Further experiments with Pygo-Lgs fusions instead demonstrated that the crucial role of the PHD is to provide an interaction motif to bind Lgs. Our results reveal an interesting evolutionary dichotomy in Pygo structure-function, as well as evidence underpinning the chain of adaptors model.
-
bcl9 2 binds arm β catenin in a tyr142 independent manner and requires Pygopus for its function in wg wnt signaling
Mechanisms of Development, 2007Co-Authors: Raymond Hoffmans, Konrad BaslerAbstract:The Wingless (Wg)/Wnt signal transduction pathway controls fundamental processes during animal development. Deregulation of the Wg/Wnt pathway has been causally linked to several forms of cancer, most notably to colorectal cancer. In response to Wg/Wnt signaling, Armadillo/beta-catenin associates in the nucleus with DNA bound TCF and several co-factors, among them Legless/BCL9, which provides a link to Pygopus. Recently, the second vertebrate homologue of Legless, BCL9-2 (or B9L), was characterized and proposed to mediate Wnt signaling in a Pygopus-independent manner, by binding to a Tyrosine-142-phosphorylated form of beta-catenin. Here we examine the role of Tyrosine-142 phosphorylation in several assays and find that it is neither important for the recruitment of BCL9-2, nor for the transcriptional activity of beta-catenin in cultured mammalian cells, nor in Drosophila for Wg signaling activity in vivo. Furthermore, we demonstrate that BCL9-2 can functionally replace Lgs both in cultured cells as well as in vivo and that this rescue activity depends on the ability of BCL9-2 to bind Pygo. Our results do not show a significant functional difference between BCL9-2 and BCL9 but rather suggest that the two proteins represent evolutionary duplicates of Legless, which have acquired distinct expression patterns while acting in a largely redundant manner.
-
parafibromin hyrax activates wnt wg target gene transcription by direct association with beta catenin armadillo
Cell, 2006Co-Authors: Christian Mosimann, George Hausmann, Konrad BaslerAbstract:The Wnt pathway controls cell fates, tissue homeostasis, and cancer. Its activation entails the association of beta-catenin with nuclear TCF/LEF proteins and results in transcriptional activation of target genes. The mechanism by which nuclear beta-catenin controls transcription is largely unknown. Here we genetically identify a novel Wnt/Wg pathway component that mediates the transcriptional outputs of beta-catenin/Armadillo. We show that Drosophila Hyrax and its human ortholog, Parafibromin, components of the Polymerase-Associated Factor 1 (PAF1) complex, are required for nuclear transduction of the Wnt/Wg signal and bind directly to the C-terminal region of beta-catenin/Armadillo. Moreover, we find that the transactivation potential of Parafibromin/Hyrax depends on the recruitment of Pygopus to beta-catenin/Armadillo. Our results assign to the tumor suppressor Parafibromin an unexpected role in Wnt signaling and provide a molecular mechanism for Wnt target gene control, in which the nuclear Wnt signaling complex directly engages the PAF1 complex, thereby controlling transcriptional initiation and elongation by RNA Polymerase II.
Mariann Bienz - One of the best experts on this subject based on the ideXlab platform.
-
rotational symmetry of the structured chip ldb ssdp core module of the wnt enhanceosome
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Miha Renko, Marc Fiedler, Trevor J Rutherford, Jonas V Schaefer, Andreas Pluckthun, Mariann BienzAbstract:The Chip/LIM-domain binding protein (LDB)-single-stranded DNA-binding protein (SSDP) (ChiLS) complex controls numerous cell-fate decisions in animal cells, by mediating transcription of developmental control genes via remote enhancers. ChiLS is recruited to these enhancers by lineage-specific LIM-domain proteins that bind to its Chip/LDB subunit. ChiLS recently emerged as the core module of the Wnt enhanceosome, a multiprotein complex that primes developmental control genes for timely Wnt responses. ChiLS binds to NPFxD motifs within Pygopus (Pygo) and the Osa/ARID1A subunit of the BAF chromatin remodeling complex, which could synergize with LIM proteins in tethering ChiLS to enhancers. Chip/LDB and SSDP both contain N-terminal dimerization domains that constitute the bulk of their structured cores. Here, we report the crystal structures of these dimerization domains, in part aided by DARPin chaperones. We conducted systematic surface scanning by structure-designed mutations, followed by in vitro and in vivo binding assays, to determine conserved surface residues required for binding between Chip/LDB, SSDP, and Pygo-NPFxD. Based on this, and on the 4:2 (SSDP-Chip/LDB) stoichiometry of ChiLS, we derive a highly constrained structural model for this complex, which adopts a rotationally symmetrical SSDP2-LDB2-SSDP2 architecture. Integrity of ChiLS is essential for Pygo binding, and our mutational analysis places the NPFxD pockets on either side of the Chip/LDB dimer, each flanked by an SSDP dimer. The symmetry and multivalency of ChiLS underpin its function as an enhancer module integrating Wnt signals with lineage-specific factors to operate context-dependent transcriptional switches that are pivotal for normal development and cancer.
-
a role of Pygopus as an anti repressor in facilitating wnt dependent transcription
Proceedings of the National Academy of Sciences of the United States of America, 2008Co-Authors: Juliusz Mieszczanek, Mariann BienzAbstract:Wnt/β-catenin signaling controls animal development and tissue homeostasis, and is also an important cancer pathway. Pygopus (Pygo) is a conserved nuclear Wnt signaling component that is essential for Wingless-induced transcription throughout Drosophila development. It associates with Armadillo/β-catenin and T cell factor (TCF) through the Legless/BCL9 adaptor, but its molecular function in TCF-mediated transcription is unknown. Here, we use a groucho-null allele to show that Groucho represses Wingless target genes during Drosophila development. Interestingly, groucho pygo double-mutants revealed that Pygo is not obligatory for transcriptional and phenotypic Wingless signaling outputs if the interaction between Groucho and Drosophila TCF is compromised genetically. Pygo function is also non-essential for Wingless outputs in the absence of other transcriptional antagonists of Wingless signaling. This indicates an anti-repressor function of Pygo: we propose that Pygo predisposes Drosophila TCF target genes for rapid Wingless-induced transcription, or that it protects them against premature shut-down.
-
wingless independent association of Pygopus with dtcf target genes
Current Biology, 2007Co-Authors: Mariann BienzAbstract:The Wnt signaling pathway controls numerous cell fates during animal development. Its inappropriate activity can lead to cancer in many human tissues. A key effector of the canonical Wnt pathway is β-catenin (or Drosophila Armadillo), a highly unstable phosphorylated protein that shuttles rapidly between nucleus and cytoplasm. Wnt signaling inhibits its phosphorylation and degradation; this allows it to associate with TCF/LEF factors bound to Wnt target genes and to stimulate their transcription by recruiting chromatin modifying and remodeling factors. The transcriptional activity of Armadillo/β-catenin also depends on Pygopus (Pygo), a nuclear protein with which it associates through the Legless/BCL9 adaptor. It has been proposed that Pygo associates with TCF target genes during Wnt signaling through Armadillo and Legless to recruit a transcriptional coactivator through its Nbox motif. Here, we report that Pygo is associated constitutively with dTCF target genes in Drosophila salivary glands and tissue-culture cells. Our evidence indicates that this association depends on dTCF and on the Nbox motif of Pygo, but not on Legless. We thus propose an alternative model according to which Pygo functions at the onset of Wnt signaling, or at low signaling levels, to capture Armadillo at dTCF target genes, thus enabling the interaction between Armadillo and dTCF and, consequently, the Armadillo-mediated recruitment of transcriptional coactivators.
-
Pygopus and legless target armadillo β catenin to the nucleus to enable its transcriptional co activator function
Nature Cell Biology, 2004Co-Authors: Fiona M Townsley, Adam Cliffe, Mariann BienzAbstract:Pygopus and Legless target Armadillo/β-catenin to the nucleus to enable its transcriptional co-activator function
-
Pygopus and legless target armadillo beta catenin to the nucleus to enable its transcriptional co activator function
Nature Cell Biology, 2004Co-Authors: Fiona M Townsley, Adam Cliffe, Mariann BienzAbstract:Pygopus and Legless target Armadillo/β-catenin to the nucleus to enable its transcriptional co-activator function
Kenneth R Kao - One of the best experts on this subject based on the ideXlab platform.
-
abstract 620 evidence for combination tamoxifen and betulinic acid to treat hormone responsive and unresponsive breast cancer by attenuation of Pygopus expression
Cancer Research, 2014Co-Authors: Youlian Tzenov, Cathy Popadiuk, Philip Andrews, Kenneth R KaoAbstract:The presence of the estrogen and progesterone hormone receptors (ER and PR) in advanced breast cancer tumour nuclei is predictive for response to hormone disruptive therapy. However, the accuracy of ER and PR testing can be variable and although patients receive significant benefit from hormone therapy, they ultimately become refractory to treatment. The chromatin remodeling protein: human Pygopus2 (hPygo2), is important for oncogenic growth and cell cycle progression and may serve as a diagnostic or targetable biomarker for breast cancer. Here we demonstrate that ER-alpha (Erα)−Sp1 transcription factor (Sp1) complexes associate with chromatin at adjacent motifs within the hPygo2 promoter in both hormone receptor positive and negative breast cancer cells. Erα agonists induced, while antagonists inhibited hPygo2 mRNA and protein expression. Erα and Sp1 occupancy at the hPygo2 promoter required intact promoter binding sites and functional DNA binding domains. Estrogen (E2) increased, while Fulvestrant decreased, Erα binding to the hPygo2 promoter with no effect on Sp1. Furthermore, Sp1-directed siRNA reduced Sp1 occupancy at the hPygo2 promoter and decreased hPygo2 mRNA and protein expression in both Erα-expressing (+) and Erα-nonexpressing (-) cells. Betulinic acid, an Sp1 inhibitor, caused cell cycle arrest, reduced Sp1 binding to the hPygo2 promoter and reduced hPygo2 expression in Erα- cell lines. The activation of hPygo2 expression either cooperatively or independently by Erα and Sp1 suggests their potential diagnostic and therapeutic benefit for both hormone responsive and unresponsive breast cancer. Citation Format: Youlian Tzenov, Philip Andrews, Cathy Popadiuk, Kenneth R. Kao. Evidence for combination tamoxifen and betulinic acid to treat hormone responsive- and unresponsive breast cancer by attenuation of Pygopus expression. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 620. doi:10.1158/1538-7445.AM2014-620
-
evidence of a novel role for Pygopus in rrna transcription
Biochemical Journal, 2013Co-Authors: Phillip G P Andrews, Youlian Tzenov, Catherine Popadiuk, Kenneth R KaoAbstract:Increased protein synthesis during cell proliferation is accompanied by a compensatory increase in efficient ribosome production, but the mechanisms by which cells adapt to this requirement are not fully understood. In the present study, we demonstrate evidence that Pygo (Pygopus), a protein originally identified as a core component of the Wnt-β-catenin transcription complex is also involved in rRNA transcription during cancer cell growth. Pygo was detected in the nucleoli of several transformed cell lines and was associated with treacle and UBF (upstream binding factor), proteins that are essential for ribosome biogenesis in development and cancer. Pygo was also detected at the ribosomal gene promoter along with core components of the rDNA (ribosomal DNA) transcription complex. RNAi (RNA interference)-mediated depletion of hPygo2 (human Pygo 2) reduced histone H4 acetylation at the rDNA promoter, down-regulated rRNA production, and induced growth arrest in both p53-positive and -negative cells. In p53-positive cells, hPygo2 knockdown triggered the ribosomal stress pathway, culminating in p53-dependent growth arrest at G1-phase of the cell cycle. The results of the present study suggest a novel involvement of Pygo in the promotion of rRNA transcription in cancer cells.
-
a co dependent requirement of xbcl9 and Pygopus for embryonic body axis development in xenopus
Developmental Dynamics, 2009Co-Authors: Mark W Kennedy, Phillip G P Andrews, Janet Heasman, Sangwook Cha, Emmanuel Tadjuidje, Kenneth R KaoAbstract:The Wnt/β-catenin transcriptional activation complex requires the adapter protein Pygopus (Pygo), which links the basal transcription machinery to β-catenin, by its association with legless (Lgs)/ B-cell lymphoma-9 (Bcl9). Pygo was shown to be required for development in vertebrates, but the role of Lgs/Bcl9 is unknown. We identified an amphibian orthologue of Lgs/Bcl9, XBcl9, which interacted biochemically with Xβ-catenin and XPygo2. The body axis promoting ability of Xβ-catenin was diminished when residues required for its interaction with XBcl9 were mutated. In blastula embryos, XBcl9 was transiently preferentially expressed in nuclei of dorsoanterior cells and ectopically expressed XBcl9 required XPygo2 to localize to nuclei. Furthermore, while neither XBcl9 nor XPygo2 alone affected development when ectopically expressed, both were required to induce supernumerary axis and dorsal gene activation. Like XPygo2, depletion of maternal XBcl9 alone caused dorsal defects. These results indicated an essential role of the Pygo-Bcl9 duet in vertebrate body axis formation. Developmental Dynamics 239:271–283, 2010. © 2009 Wiley-Liss, Inc.
-
the transcriptional activity of Pygopus is enhanced by its interaction with camp response element binding protein creb binding protein
Biochemical Journal, 2009Co-Authors: Phillip G P Andrews, Cathy Popadiuk, Kenneth R KaoAbstract:Pygopus is a core component of the β-catenin/TCF (T-cell factor) transcriptional activation complex required for the expression of canonical Wnt target genes. Recent evidence suggests that Pygopus could interpret histone methylation associated with target genes and it was shown to be required for histone acetylation. The involvement of a specific acetyltransferase, however, was not determined. In this report, we demonstrate that Pygopus can interact with the HAT (histone acetyltransferase) CBP [CREB (cAMP-responsive-element-binding protein)-binding protein]. The interaction is via the NHD (N-terminal homology domain) of Pygopus, which binds to two regions in the vicinity of the HAT domain of CBP. Transfected and endogenous hPygo2 (human Pygopus2) and CBP proteins co-immunoprecipitate in HEK-293 (human embryonic kidney 293) cells and both proteins co-localize in SW480 colorectal cancer cells. The interaction with CBP also enhances both DNA-tethered and TCF/LEF1 (lymphoid enhancing factor 1)-dependent transcriptional activity of Pygopus. Furthermore, immunoprecipitated Pygopus protein complexes displayed CBP-dependent histone acetyltransferase activity. Our data support a model in which the NHD region of Pygopus is required to augment TCF/β-catenin-mediated transcriptional activation by a mechanism that includes both transcriptional activation and histone acetylation resulting from the recruitment of the CBP histone acetyltransferase.
-
abstract 1513 recruitment of histone acetyltransferase activity by the n terminal homology domain of Pygopus augments tcf dependent transcriptional activation
Cancer Research, 2009Co-Authors: Phillip G P Andrews, Kenneth R Kao, Catherine PopadiukAbstract:Pygopus is a core component of the beta-catenin/TCF transcriptional activation complex, hypothesized to augment target gene expression by interpreting and modifying the local histone code. Pygopus is essential for development of the early embryo for both Wnt-dependent and Wnt-independent activity and is also required for breast and epithelial ovarian cancer cell growth. The Pygopus protein consists of two conserved domains: a plant homeo domain (PHD), which interacts with the Legless (lgs) adapter protein linking it to the beta-catenin/TCF complex, and an N-terminal homology domain (NHD). The NHD is essential for transcriptional activity, but evidence is lacking on its interaction with other proteins. We now demonstrate that the interaction of Pygopus with histone acetyltransferase (HAT) family members via specific residues in its N-terminal homology domain (NHD) is required to enhance beta-catenin/TCF mediated transcription. The HAT family member CREB Binding Protein (CBP), a component of the beta-catenin/TCF complex, augmented Pygopus-mediated transcription from both TCF/LEF-specific reporter genes, as well as from DNA-tethered Pygopus. Furthermore, immunoprecipitated Pygopus protein complexes displayed CBP-dependent histone acetyltransferase activity. Our data support a model in which the chromatin relaxation requirement in TCF/beta-catenin-mediated transcriptional activation is fulfilled by recruitment of the histone acetyltransferase CBP by Pygopus. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1513.
Thimios A Mitsiadis - One of the best experts on this subject based on the ideXlab platform.
-
a cytoplasmic role of wnt β catenin transcriptional cofactors bcl9 bcl9l and Pygopus in tooth enamel formation
Science Signaling, 2017Co-Authors: Claudio Cantu, Konrad Basler, George Hausmann, Pierfrancesco Pagella, Tania D Shajiei, Dario Zimmerli, Tomas Valenta, Thimios A MitsiadisAbstract:Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate wit ...
-
a cytoplasmic role of wnt β catenin transcriptional cofactors bcl9 bcl9l and Pygopus in tooth enamel formation
Science Signaling, 2017Co-Authors: Claudio Cantu, Konrad Basler, George Hausmann, Pierfrancesco Pagella, Tania D Shajiei, Dario Zimmerli, Tomas Valenta, Thimios A MitsiadisAbstract:Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate with β-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind β-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. We showed that Bcl9 and Bcl9l function in the cytoplasm during tooth enamel formation in a manner that is independent of Wnt-stimulated β-catenin-dependent transcription. Bcl9, Bcl9l, and Pygo2 localized mainly to the cytoplasm of the epithelial-derived ameloblasts, the cells responsible for enamel production. In ameloblasts, Bcl9 interacted with proteins involved in enamel formation and proteins involved in exocytosis and vesicular trafficking. Conditional deletion of both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in mice produced teeth with defective enamel that was bright white and deficient in iron, which is reminiscent of human tooth enamel pathologies. Overall, our data revealed that these proteins, originally defined through their function as β-catenin transcriptional cofactors, function in odontogenesis through a previously uncharacterized cytoplasmic mechanism, revealing that they have roles beyond that of transcriptional cofactors.
George Hausmann - One of the best experts on this subject based on the ideXlab platform.
-
a cytoplasmic role of wnt β catenin transcriptional cofactors bcl9 bcl9l and Pygopus in tooth enamel formation
Science Signaling, 2017Co-Authors: Claudio Cantu, Konrad Basler, George Hausmann, Pierfrancesco Pagella, Tania D Shajiei, Dario Zimmerli, Tomas Valenta, Thimios A MitsiadisAbstract:Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate wit ...
-
a cytoplasmic role of wnt β catenin transcriptional cofactors bcl9 bcl9l and Pygopus in tooth enamel formation
Science Signaling, 2017Co-Authors: Claudio Cantu, Konrad Basler, George Hausmann, Pierfrancesco Pagella, Tania D Shajiei, Dario Zimmerli, Tomas Valenta, Thimios A MitsiadisAbstract:Wnt-stimulated β-catenin transcriptional regulation is necessary for the development of most organs, including teeth. Bcl9 and Bcl9l are tissue-specific transcriptional cofactors that cooperate with β-catenin. In the nucleus, Bcl9 and Bcl9l simultaneously bind β-catenin and the transcriptional activator Pygo2 to promote the transcription of a subset of Wnt target genes. We showed that Bcl9 and Bcl9l function in the cytoplasm during tooth enamel formation in a manner that is independent of Wnt-stimulated β-catenin-dependent transcription. Bcl9, Bcl9l, and Pygo2 localized mainly to the cytoplasm of the epithelial-derived ameloblasts, the cells responsible for enamel production. In ameloblasts, Bcl9 interacted with proteins involved in enamel formation and proteins involved in exocytosis and vesicular trafficking. Conditional deletion of both Bcl9 and Bcl9l or both Pygo1 and Pygo2 in mice produced teeth with defective enamel that was bright white and deficient in iron, which is reminiscent of human tooth enamel pathologies. Overall, our data revealed that these proteins, originally defined through their function as β-catenin transcriptional cofactors, function in odontogenesis through a previously uncharacterized cytoplasmic mechanism, revealing that they have roles beyond that of transcriptional cofactors.
-
the phd domain is required to link drosophila Pygopus to legless beta catenin and not to histone h3
Mechanisms of Development, 2009Co-Authors: Roman Kessler, George Hausmann, Konrad BaslerAbstract:In Drosophila Pygopus (Pygo) and Legless (Lgs)/BCL9 are integral components of the nuclear Wnt/Wg signaling machine. Despite intense research, ideas that account for their mode of action remain speculative. One proposition, based on a recently discovered function of PHD fingers, is that Pygo, through its PHD, may decipher the histone code. We found that human, but not Drosophila, Pygo robustly interacts with a histone-H3 peptide methylated at lysine-4. The different binding behavior is due to a single amino acid change that appears unique to Drosophilidae Pygo proteins. Rescue experiments with predicted histone binding mutants showed that in Drosophila the ability to bind histones is not essential. Further experiments with Pygo-Lgs fusions instead demonstrated that the crucial role of the PHD is to provide an interaction motif to bind Lgs. Our results reveal an interesting evolutionary dichotomy in Pygo structure-function, as well as evidence underpinning the chain of adaptors model.
-
parafibromin hyrax activates wnt wg target gene transcription by direct association with beta catenin armadillo
Cell, 2006Co-Authors: Christian Mosimann, George Hausmann, Konrad BaslerAbstract:The Wnt pathway controls cell fates, tissue homeostasis, and cancer. Its activation entails the association of beta-catenin with nuclear TCF/LEF proteins and results in transcriptional activation of target genes. The mechanism by which nuclear beta-catenin controls transcription is largely unknown. Here we genetically identify a novel Wnt/Wg pathway component that mediates the transcriptional outputs of beta-catenin/Armadillo. We show that Drosophila Hyrax and its human ortholog, Parafibromin, components of the Polymerase-Associated Factor 1 (PAF1) complex, are required for nuclear transduction of the Wnt/Wg signal and bind directly to the C-terminal region of beta-catenin/Armadillo. Moreover, we find that the transactivation potential of Parafibromin/Hyrax depends on the recruitment of Pygopus to beta-catenin/Armadillo. Our results assign to the tumor suppressor Parafibromin an unexpected role in Wnt signaling and provide a molecular mechanism for Wnt target gene control, in which the nuclear Wnt signaling complex directly engages the PAF1 complex, thereby controlling transcriptional initiation and elongation by RNA Polymerase II.
