Biomedical subjects

Mariann Bienz

Publications and source records attributed to Mariann Bienz.

8 recordsLinked to original sources

PubMed2003

A role of Dishevelled in relocating Axin to the plasma membrane during wingless signaling.

Wnt signaling causes changes in gene transcription that are pivotal for normal and malignant development. A key effector of the canonical Wnt pathway is beta-catenin, or Drosophila Armadillo. In the absence of Wnt ligand, beta-catenin is phosphorylated by the Axin complex, which earmarks it for rapid degradation by the ubiquitin system. Axin acts as a scaffold in this complex, to assemble beta-catenin substrate and kinases (casein kinase I [CKI] and glycogen synthase kinase 3 beta [GSK3]). The Adenomatous polyposis coli (APC) tumor suppressor also binds to the Axin complex, thereby promoting the degradation of beta-catenin. In Wnt signaling, this complex is inhibited; as a consequence, beta-catenin accumulates and binds to TCF proteins to stimulate the transcription of Wnt target genes. Wnt-induced inhibition of the Axin complex depends on Dishevelled (Dsh), a cytoplasmic protein that can bind to Axin, but the mechanism of this inhibition is not understood. Here, we show that Wingless signaling causes a striking relocation of Drosophila Axin from the cytoplasm to the plasma membrane. This relocation depends on Dsh. It may permit the subsequent inactivation of the Axin complex by Wingless signaling.

Adaptor Proteins, Signal Transducing↗

PubMed2003

APC.

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Adenomatous Polyposis Coli↗

PubMed2003

Nuclear export of the APC tumour suppressor controls beta-catenin function in transcription.

The adenomatous polyposis coli (APC) protein is inactivated in most colorectal tumours. APC loss is an early event in tumorigenesis, and causes an increase of nuclear beta-catenin and its transcriptional activity. This is thought to be the driving force for tumour progression. APC shuttles in and out of the nucleus, but the functional significance of this has been controversial. Here, we show that APC truncations are nuclear in colorectal cancer cells and adenocarcinomas, and this correlates with loss of centrally located nuclear export signals. These signals confer efficient nuclear export as measured directly by fluorescence loss in photobleaching (FLIP), and they are critical for the function of APC in reducing the transcriptional activity of beta-catenin in complementation assays of APC mutant colorectal cancer cells. Importantly, targeting a functional APC construct to the nucleus causes a striking nuclear accumulation of beta-catenin without changing its transcriptional activity. Our evidence indicates that the rate of nuclear export of APC, rather than its nuclear import or steady-state levels, determines the transcriptional activity of beta-catenin.

Active Transport, Cell Nucleus↗

PubMed2003

Armadillo/beta-catenin signals in the nucleus--proof beyond a reasonable doubt?

Wnt signalling results in transcriptional stimulation of genes controlling normal and malignant development. A key effector of the canonical Wnt pathway is beta-catenin (also known as Drosophila melanogaster Armadillo (Arm)), thought to function as a nuclear co-activator of TCF transcription factors. This has been challenged by unexpected observations of membrane-bound Arm/beta-catenin signalling activity. Plausible explanations allow these observations to be reconciled with the large body of evidence supporting a nuclear function of Arm/beta-catenin.

Animals↗

PubMed2002

The transcriptional repressor Brinker antagonizes Wingless signaling.

In the embryonic midgut of Drosophila, Wingless (Wg) signaling elicits threshold-specific transcriptional response, that is, low-signaling levels activate target genes, whereas high-signaling levels repress them. Wg-mediated repression of the HOX gene Ultrabithorax (Ubx) is conferred by a response sequence within the Ubx B midgut enhancer, called WRS-R. It further depends on the Teashirt (Tsh) repressor, which acts through the WRS-R without binding to it. Here, we show that Wg-mediated repression of Ubx B depends on Brinker, which binds to the WRS-R. Furthermore, Brinker blocks transcriptional activation by ubiquitous Wg signaling. Brinker binds to Tsh in vitro, recruits Tsh to the WRS-R, and we find mutual physical interactions between Brinker, Tsh, and the corepressor dCtBP. This suggests that the three proteins may form a ternary repressor complex at the WRS-R to quench the activity of the nearby-bound dTCF/Armadillo transcription complex. Finally, brinker and tsh produce similar mutant phenotypes in the ventral epidermis, and double mutants mimic overactive Wg signaling in this tissue. This suggests that Brinker may have a widespread function in antagonizing Wg signaling.

Alcohol Oxidoreductases↗

PubMed2002

A Drosophila APC tumour suppressor homologue functions in cellular adhesion.

Adenomatous polyposis coli (APC) is an important tumour suppressor in the intestinal epithelium. Its function in reducing nuclear beta-catenin and T-cell factor (TCF)-mediated transcription is conserved from Drosophila to mammals. But APC proteins are also associated with the plasma membrane. Here, we show that mutational inactivation of Drosophila E-APC causes delocalization of Armadillo (the Drosophila beta-catenin) but not DE-cadherin from adhesive plasma membranes. Extensive gaps between these membranes are visible at the ultrastructural level. The oocyte is also mislocalized in E-APC mutant egg chambers, a phenotype that results from a failure of cadherin-based adhesion. These results indicate that Drosophila APC functions in cellular adhesion; these results could have implications for colorectal adenoma formation and tumour progression in humans.

Adenomatous Polyposis Coli↗

PubMed2002

A new nuclear component of the Wnt signalling pathway.

The Wnt signalling pathway is pivotal in normal and malignant development. A key effector is Armadillo (Arm)/beta-catenin, which functions with TCF to transcribe Wnt target-genes. Here, we report the discovery of pygopus (pygo), whose mutant phenotypes specifically mimic loss-of-Wingless (Wg) signalling. pygo is required for dTCF-mediated transcription, but not for Wg-induced stabilization of Arm. Pygo is a nuclear protein that is found in a complex with Arm in vivo. Humans possess two Pygo proteins, both of which are required for TCF-mediated transcription in colorectal cancer cells. The presence of a PHD domain implicates Pygo proteins in a chromatin-related function, and we propose that they mediate chromatin access to TCF or Arm/beta-catenin.

Adaptor Proteins, Signal Transducing↗

PubMed2002

The subcellular destinations of APC proteins.

Adenomatous polyposis coli (APC) is an important tumour suppressor in the human colon, and is conserved in various organisms. Its best understood function is the destabilization of beta-catenin, a key effector of the Wnt signalling pathway. APC proteins are highly motile, and shuttle between several subcellular destinations. These destinations have prompted the discovery of new functions for the APC proteins, and this multitasking of APC might explain why its loss often leads to cancer.

Adenomatous Polyposis Coli↗