Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions.

ABSTRACT: beta-Catenin controls both cadherin-mediated cell adhesion and activation of Wnt target genes. We demonstrate here that the beta-catenin-binding protein BCL9-2, a homolog of the human proto-oncogene product BCL9, induces epithelial-mesenchymal transitions of nontransformed cells and increases beta-catenin-dependent transcription. RNA interference of BCL9-2 in carcinoma cells induces an epithelial phenotype and translocates beta-catenin from the nucleus to the cell membrane. The switch between beta-catenin's adhesive and transcriptional functions is modulated by phosphorylation of Tyr 142 of beta-catenin, which favors BCL9-2 binding and precludes interaction with alpha-catenin. During zebrafish embryogenesis, BCL9-2 acts in the Wnt8-signaling pathway and regulates mesoderm patterning.

SUBMITTER: Brembeck FH

PROVIDER: S-EPMC517514 | biostudies-literature | 2004 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Essential role of BCL9-2 in the switch between beta-catenin's adhesive and transcriptional functions.

Brembeck Felix H FH Schwarz-Romond Thomas T Bakkers Jeroen J Wilhelm Sabine S Hammerschmidt Matthias M Birchmeier Walter W

Genes & development 20040901 18

beta-Catenin controls both cadherin-mediated cell adhesion and activation of Wnt target genes. We demonstrate here that the beta-catenin-binding protein BCL9-2, a homolog of the human proto-oncogene product BCL9, induces epithelial-mesenchymal transitions of nontransformed cells and increases beta-catenin-dependent transcription. RNA interference of BCL9-2 in carcinoma cells induces an epithelial phenotype and translocates beta-catenin from the nucleus to the cell membrane. The switch between be ...[more]

PMID: 15371335

Similar Datasets

BCL9/STAT3 regulation of transcriptional enhancer networks promote DCIS progression.

Project description:The molecular processes by which some human ductal carcinoma in situ (DCIS) lesions advance to the more aggressive form, while others remain indolent, are largely unknown. Experiments utilizing a patient-derived (PDX) DCIS Mouse INtraDuctal (MIND) animal model combined with ChIP-exo and RNA sequencing revealed that the formation of protein complexes between B Cell Lymphoma-9 (BCL9), phosphoserine 727 STAT3 (PS-727-STAT3) and non-STAT3 transcription factors on chromatin enhancers lead to subsequent transcription of key drivers of DCIS malignancy. Downregulation of two such targets, integrin β3 and its associated metalloproteinase, MMP16, resulted in a significant inhibition of DCIS invasive progression. Finally, in vivo targeting of BCL9, using rosemary extract, resulted in significant inhibition of DCIS malignancy in both cell line and PDX DCIS MIND animal models. As such, our studies provide compelling evidence for future testing of rosemary extract as a chemopreventive agent in breast cancer.

| S-EPMC7181646 | biostudies-literature

PARP-14 functions as a transcriptional switch for Stat6-dependent gene activation.

Project description:A subset of poly ADP-ribose polymerases (PARP) that also contain macro domains regulate transcription. One such macro PARP, PARP-14 alters interleukin 4 (IL-4) and Stat6-dependent transcription. Stat6, activated by IL-4 plays an important role in T helper cell immunity and B cell responses. Here we define the mechanism by which PARP-14 regulates Stat6-activated transcription. Under non-stimulating conditions, PARP-14 recruits HDAC 2 and 3 to IL-4 responsive promoters. In the presence of IL-4, PARP-14 promotes efficient binding of Stat6 to its target genes. Moreover, HDAC 2 and 3 are released from the promoter with an IL-4 signal, this is aided by the ADP-ribosylation of the HDACs by PARP-14. The HDACs and PARP-14 get replaced by coactivators containing HAT activity. Based on these observations we put forth a mechanism in which PARP-14 functions as a transcriptional switch for Stat6-dependent gene induction. Thus, in the absence of a signal PARP-14 acts as a transcriptional repressor by recruiting HDACs. In contrast, in the presence of IL-4 the catalytic activity of PARP-14 facilitates Stat6 binding to the promoter, and release of HDACs so as to activate transcription.

| S-EPMC3023471 | biostudies-literature

Bacterial cell cycle and growth phase switch by the essential transcriptional regulator CtrA.

Project description:Many bacteria acquire dissemination and virulence traits in G1-phase. CtrA, an essential and conserved cell cycle transcriptional regulator identified in the dimorphic alpha-proteobacterium Caulobacter crescentus, first activates promoters in late S-phase and then mysteriously switches to different target promoters in G1-phase. We uncovered a highly conserved determinant in the DNA-binding domain (DBD) of CtrA uncoupling this promoter switch. We also show that it reprograms CtrA occupancy in stationary cells inducing a (p)ppGpp alarmone signal perceived by the RNA polymerase beta subunit. A simple side chain modification in a critical residue within the core DBD imposes opposing developmental phenotypes and transcriptional activities of CtrA and a proximal residue can direct CtrA towards activation of the dispersal (G1-phase) program. Hence, we propose that this conserved determinant in the CtrA primary structure dictates promoter reprogramming during the growth transition in other alpha-proteobacteria that differentiate from replicative cells into dispersal cells.

| S-EPMC6847485 | biostudies-literature

Hypoxia-inducible factor 1α induces osteo/odontoblast differentiation of human dental pulp stem cells via Wnt/β-catenin transcriptional cofactor BCL9.

Project description:Accelerated dental pulp mineralization is a common complication in avulsed/luxated teeth, although the mechanisms underlying this remain unclear. We hypothesized that hypoxia due to vascular severance may induce osteo/odontoblast differentiation of dental pulp stem cells (DPSCs). This study examined the role of B-cell CLL/lymphoma 9 (BCL9), which is downstream of hypoxia-inducible factor 1α (HIF1α) and a Wnt/β-catenin transcriptional cofactor, in the osteo/odontoblastic differentiation of human DPSCs (hDPSCs) under hypoxic conditions. hDPSCs were isolated from extracted healthy wisdom teeth. Hypoxic conditions and HIF1α overexpression induced significant upregulation of mRNAs for osteo/odontoblast markers (RUNX2, ALP, OC), BCL9, and Wnt/β-catenin signaling target genes (AXIN2, TCF1) in hDPSCs. Overexpression and suppression of BCL9 in hDPSCs up- and downregulated, respectively, the mRNAs for AXIN2, TCF1, and the osteo/odontoblast markers. Hypoxic-cultured mouse pulp tissue explants showed the promotion of HIF1α, BCL9, and β-catenin expression and BCL9-β-catenin co-localization. In addition, BCL9 formed a complex with β-catenin in hDPSCs in vitro. This study demonstrated that hypoxia/HIF1α-induced osteo/odontoblast differentiation of hDPSCs was partially dependent on Wnt/β-catenin signaling, where BCL9 acted as a key mediator between HIF1α and Wnt/β-catenin signaling. These findings may reveal part of the mechanisms of dental pulp mineralization after traumatic dental injury.

| S-EPMC8758693 | biostudies-literature

An RNA enhancer in a phage transcriptional antitermination complex functions as a structural switch.

Project description:Antitermination protein N regulates the transcriptional program of phage lambda through recognition of RNA enhancer elements. Binding of an arginine-rich peptide to one face of an RNA hairpin organizes the other, which in turn binds to the host antitermination complex. The induced RNA structure mimics a GNRA hairpin, an organizational element of rRNA and ribozymes. The two faces of the RNA, bridged by a sheared GA base pair, exhibit a specific pattern of base stacking and base flipping. This pattern is extended by stacking of an aromatic amino acid side chain with an unpaired adenine at the N-binding surface. Such extended stacking is coupled to induction of a specific internal RNA architecture and is blocked by RNA mutations associated in vivo with loss of transcriptional antitermination activity. Mimicry of a motif of RNA assembly by an RNA-protein complex permits its engagement within the antitermination machinery.

| S-EPMC275392 | biostudies-literature

LATS2 suppresses oncogenic Wnt signaling by disrupting β-catenin/BCL9 interaction.

Project description:Abnormal activation of Wnt/β-catenin-mediated transcription is associated with a variety of human cancers. Here, we report that LATS2 inhibits oncogenic Wnt/β-catenin-mediated transcription by disrupting the β-catenin/BCL9 interaction. LATS2 directly interacts with β-catenin and is present on Wnt target gene promoters. Mechanistically, LATS2 inhibits the interaction between BCL9 and β-catenin and subsequent recruitment of BCL9, independent of LATS2 kinase activity. LATS2 is downregulated and inversely correlated with the levels of Wnt target genes in human colorectal cancers. Moreover, nocodazole, an antimicrotubule drug, potently induces LATS2 to suppress tumor growth in vivo by targeting β-catenin/BCL9. Our results suggest that LATS2 is not only a key tumor suppressor in human cancer but may also be an important target for anticancer therapy.

| S-EPMC3897473 | biostudies-literature

Design of triazole-stapled BCL9 α-helical peptides to target the β-catenin/B-cell CLL/lymphoma 9 (BCL9) protein-protein interaction.

Project description:The interaction between β-catenin and B-cell CLL/lymphoma 9 (BCL9), critical for the transcriptional activity of β-catenin, is mediated by a helical segment from BCL9 and a large binding groove in β-catenin. Design of potent, metabolically stable BCL9 peptides represents an attractive approach to inhibit the activity of β-catenin. In this study, we report the use of the Huisgen 1,3-dipolar cycloaddition reaction to generate triazole-stapled BCL9 α-helical peptides. The high efficiency and mild conditions of this "click" reaction combined with the ease of synthesis of the necessary unnatural amino acids allows for facile synthesis of triazole-stapled peptides. We have performed extensive optimization of this approach and identified the optimal combinations of azido and alkynyl linkers necessary for stapling BCL9 helices. The unsymmetrical nature of the triazole staple also allowed the synthesis of double-stapled BCL9 peptides, which show a marked increase in helical character and an improvement in binding affinity and metabolic stability relative to wild-type and linear BCL9 peptides. This study lays the foundation for further optimization of these triazole-stapled BCL9 peptides as potent, metabolically stable, and cell-permeable inhibitors to target the β-catenin and BCL9 interaction.

| S-EPMC3286869 | biostudies-literature

Pol II phosphorylation regulates a switch between transcriptional and splicing condensates.

Project description:The synthesis of pre-mRNA by RNA polymerase II (Pol II) involves the formation of a transcription initiation complex, and a transition to an elongation complex1-4. The large subunit of Pol II contains an intrinsically disordered C-terminal domain that is phosphorylated by cyclin-dependent kinases during the transition from initiation to elongation, thus influencing the interaction of the C-terminal domain with different components of the initiation or the RNA-splicing apparatus5,6. Recent observations suggest that this model provides only a partial picture of the effects of phosphorylation of the C-terminal domain7-12. Both the transcription-initiation machinery and the splicing machinery can form phase-separated condensates that contain large numbers of component molecules: hundreds of molecules of Pol II and mediator are concentrated in condensates at super-enhancers7,8, and large numbers of splicing factors are concentrated in nuclear speckles, some of which occur at highly active transcription sites9-12. Here we investigate whether the phosphorylation of the Pol II C-terminal domain regulates the incorporation of Pol II into phase-separated condensates that are associated with transcription initiation and splicing. We find that the hypophosphorylated C-terminal domain of Pol II is incorporated into mediator condensates and that phosphorylation by regulatory cyclin-dependent kinases reduces this incorporation. We also find that the hyperphosphorylated C-terminal domain is preferentially incorporated into condensates that are formed by splicing factors. These results suggest that phosphorylation of the Pol II C-terminal domain drives an exchange from condensates that are involved in transcription initiation to those that are involved in RNA processing, and implicates phosphorylation as a mechanism that regulates condensate preference.

| S-EPMC6706314 | biostudies-literature

Kinetic partitioning between alternative protein-protein interactions controls a transcriptional switch.

Project description:Proteins can perform completely distinct functions in response to the particular partners that they bind to. Consequently, determination of the mechanism of functional regulation in such systems requires elucidation of the mechanism switching between binding partners. The central protein of the Escherichia coli biotin regulatory system, BirA, switches between its function as a metabolic enzyme or a transcriptional repressor in response to binding either the biotin carboxyl carrier protein subunit of acetyl-CoA carboxylase or a second BirA monomer. These two protein-protein interactions are structurally mutually exclusive. The results of earlier studies suggest that the system is regulated by kinetic partitioning between the two protein-protein interactions. In this work, sedimentation velocity was employed to monitor the partitioning directly. The results indicate similar equilibrium parameters governing formation of the two protein-protein interactions. Kinetic analysis of the sedimentation velocity data indicated that holoBirA dimerization is governed by very slow forward and reverse rate constants. The slow kinetics of holoBirA dimerization combined with fluctuations in the intracellular apoBCCP pool are critical determinants in partitioning BirA between its distinct biological functions.

| S-EPMC2566847 | biostudies-literature

Cytoplasmic domain of zebrafish myelin protein zero: adhesive role depends on beta-conformation.

Project description:Solution spectroscopy studies on the cytoplasmic domain of human myelin protein zero (P0) (hP0-cyt) suggest that H-bonding between beta-strands from apposed molecules is likely responsible for the tight cytoplasmic apposition in compact myelin. As a follow-up to these findings, in the current study we used circular dichroism and x-ray diffraction to analyze the same type of model membranes previously used for hP0-cyt to investigate the molecular mechanism underlying the zebrafish cytoplasmic apposition. This space is significantly narrower in teleosts compared with that in higher vertebrates, and can be accounted for in part by the much shorter cytoplasmic domain in the zebrafish protein (zP0-cyt). Circular dichroism measurements on zP0-cyt showed similar structural characteristics to those of hP0-cyt, i.e., the protein underwent a beta-->alpha structural transition at lipid/protein (L/P) molar ratios >50, and adopted a beta-conformation at lower L/P molar ratios. X-ray diffraction was carried out on lipid vesicle solutions with zP0-cyt before and after dehydration to study the effect of protein on membrane lipid packing. Solution diffraction revealed the electron-density profile of a single membrane bilayer. Diffraction patterns of dried samples suggested a multilamellar structure with the beta-folded P0-cyt located at the intermembrane space. Our findings support the idea that the adhesive role of P0 at the cytoplasmic apposition in compact myelin depends on the cytoplasmic domain of P0 being in the beta-conformation.

| S-EPMC2072062 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data