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The WNT/β-catenin dependent transcription: A tissue-specific business.

ABSTRACT: β-catenin-mediated Wnt signaling is an ancient cell-communication pathway in which β-catenin drives the expression of certain genes as a consequence of the trigger given by extracellular WNT molecules. The events occurring from signal to transcription are evolutionarily conserved, and their final output orchestrates countless processes during embryonic development and tissue homeostasis. Importantly, a dysfunctional Wnt/β-catenin pathway causes developmental malformations, and its aberrant activation is the root of several types of cancer. A rich literature describes the multitude of nuclear players that cooperate with β-catenin to generate a transcriptional program. However, a unified theory of how β-catenin drives target gene expression is still missing. We will discuss two types of β-catenin interactors: transcription factors that allow β-catenin to localize at target regions on the DNA, and transcriptional co-factors that ultimately activate gene expression. In contrast to the presumed universality of β-catenin's action, the ensemble of available evidence suggests a view in which β-catenin drives a complex system of responses in different cells and tissues. A malleable armamentarium of players might interact with β-catenin in order to activate the right "canonical" targets in each tissue, developmental stage, or disease context. Discovering the mechanism by which each tissue-specific β-catenin response is executed will be crucial to comprehend how a seemingly universal pathway fosters a wide spectrum of processes during development and homeostasis. Perhaps more importantly, this could ultimately inform us about which are the tumor-specific components that need to be targeted to dampen the activity of oncogenic β-catenin. This article is categorized under: Cancer > Molecular and Cellular Physiology Cancer > Genetics/Genomics/Epigenetics Cancer > Stem Cells and Development.

SUBMITTER: Soderholm S

PROVIDER: S-EPMC9285942 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Estradiol may fulfill a plethora of functions in neurons, in which much of its activity is associated with its capacity to directly bind and dimerize estrogen receptors. This hormone-protein complex can either bind directly to estrogen response elements (ERE's) in gene promoters, or it may act as a cofactor at non-ERE sites interacting with other DNA-binding elements such as AP-1 or c-Jun. Many of the neuroprotective effects described for estrogen have been associated with this mode of action. However, recent evidence suggests that in addition to these "genomic effects", estrogen may also act as a more general "trophic factor" triggering cytoplasmic signals and extending the potential activity of this hormone. We demonstrated that estrogen receptor alpha associates with beta-catenin and glycogen synthase kinase 3 in the brain and in neurons, which has since been confirmed by others. Here, we show that the action of estradiol activates beta-catenin transcription in neuroblastoma cells and in primary cortical neurons. This activation is time and concentration-dependent, and it may be abolished by the estrogen receptor antagonist ICI 182780. The transcriptional activation of beta-catenin is dependent on lymphoid enhancer binding factor-1 (LEF-1) and a truncated-mutant of LEF-1 almost completely blocks estradiol TCF-mediated transcription. Transcription of a TCF-reporter in a transgenic mouse model is enhanced by estradiol in a similar fashion to that produced by Wnt3a. In addition, activation of a luciferase reporter driven by the engrailed promoter with three LEF-1 repeats was mediated by estradiol. We established a cell line that constitutively expresses a dominant-negative LEF-1 and it was used in a gene expression microarray analysis. In this way, genes that respond to estradiol or Wnt3a, sensitive to LEF-1, could be identified and validated. Together, these data demonstrate the existence of a new signaling pathway controlled by estradiol in neurons. This pathway shares some elements of the insulin-like growth factor-1/Insulin and Wnt signaling pathways, however, our data strongly suggest that it is different from that of both these ligands. These findings may reveal a set of new physiological roles for estrogens, at least in the Central Nervous System (CNS).

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The WNT/β-catenin dependent transcription: A tissue-specific business.

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