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Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription.

ABSTRACT: Canonical Wnt signaling is mediated by a molecular "switch" that regulates the transcriptional properties of the T-cell factor (TCF) family of DNA-binding proteins. Members of the myeloid translocation gene (MTG) family of transcriptional corepressors are frequently disrupted by chromosomal translocations in acute myeloid leukemia, whereas MTG16 may be inactivated in up to 40% of breast cancer and MTG8 is a candidate cancer gene in colorectal carcinoma. Genetic studies imply that this corepressor family may function in stem cells. Given that mice lacking Myeloid Translocation Gene Related-1 (Mtgr1) fail to maintain the secretory lineage in the small intestine, we surveyed transcription factors that might recruit Mtgr1 in intestinal stem cells or progenitor cells and found that MTG family members associate specifically with TCF4. Coexpression of beta-catenin disrupted the association between these corepressors and TCF4. Furthermore, when expressed in Xenopus embryos, MTG family members inhibited axis formation and impaired the ability of beta-catenin and XLef-1 to induce axis duplication, indicating that MTG family members act downstream of beta-catenin. Moreover, we found that c-Myc, a transcriptional target of the Wnt pathway, was overexpressed in the small intestines of mice lacking Mtgr1, thus linking inactivation of Mtgr1 to the activation of a potent oncogene.

SUBMITTER: Moore AC

PROVIDER: S-EPMC2223385 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Backgroundbeta-catenin is a key mediator of the canonical Wnt pathway as it associates with members of the T-cell factor (TCF) family at Wnt-responsive promoters to drive the transcription of Wnt target genes. Recently, we showed that Rac1 GTPase synergizes with beta-catenin to increase the activity of a TCF-responsive reporter. This synergy was dependent on the nuclear presence of Rac1, since inhibition of its nuclear localization effectively abolished the stimulatory effect of Rac1 on TCF-responsive reporter activity. We hypothesised that Rac1 plays a direct role in enhancing the transcription of endogenous Wnt target genes by modulating the beta-catenin/TCF transcription factor complex.ResultsWe employed chromatin immunoprecipitation studies to demonstrate that Rac1 associates with the beta-catenin/TCF complex at Wnt-responsive promoters of target genes. This association served to facilitate transcription, since overexpression of active Rac1 augmented Wnt target gene activation, whereas depletion of endogenous Rac1 by RNA interference abrogated this effect. In addition, the Rac1-specific exchange factor, Tiam1, potentiated the stimulatory effects of Rac1 on the canonical Wnt pathway. Tiam1 promoted the formation of a complex containing Rac1 and beta-catenin. Furthermore, endogenous Tiam1 associated with endogenous beta-catenin, and this interaction was enhanced in response to Wnt3a stimulation. Intriguingly, Tiam1 was recruited to Wnt-responsive promoters upon Wnt3a stimulation, whereas Rac1 was tethered to TCF binding elements in a Wnt-independent manner.ConclusionTaken together, our results suggest that Rac1 and the Rac1-specific activator Tiam1 are components of transcriptionally active beta-catenin/TCF complexes at Wnt-responsive promoters, and the presence of Rac1 and Tiam1 within these complexes serves to enhance target gene transcription. Our results demonstrate a novel functional mechanism underlying the cross-talk between Rac1 and the canonical Wnt signalling pathway.

Project description:BACKGROUND:Patient- and family-centered care (PFCC) is increasingly linked to improved communication, care quality, and patient decision making. However, in order to consistently implement and study PFCC, health care systems and researchers need a solid evidentiary base. Most current definitions and models of PFCC are broad and conceptual, and difficult to translate into measurable behaviors and actions. This paper provides a brief overview of all actions that focus group respondents associated with PFCC in ambulatory (outpatient) care settings and then explores actions associated with the concept of "dignity and respect" in greater detail. METHODS:We conducted nine focus groups with patients, family members, and physicians in three metropolitan regions across the United States. Group discussions were transcribed and analyzed using a thematic analysis approach. RESULTS:We identified 14 domains and 47 specific actions that patients, family members, and physicians associate with PFCC. In addition to providing a detailed matrix of these domains and actions, this paper details the actions associated with the "dignity and respect" concept. Key domains identified under "dignity and respect" include: 1) building relationships, 2) providing individualized care, and 3) respecting patients' time. Within these domains we identified specific actions that break down these abstract ideas into explicit and measurable units such as taking time, listening, including family, and minimizing wait times. We identified 9, 6, and 3 specific actions associated, respectively, with building relationships, providing individualized care, and respecting patients' time. CONCLUSIONS:Our work fills a critical gap in our ability to understand and measure PFCC in ambulatory care settings by breaking down abstract concepts about PFCC into specific measurable actions. Our findings can be used to support research on how PFCC affects clinical outcomes and develop innovative tools and policies to support PFCC.

Project description:BackgroundWnt/β-catenin signaling is often portrayed as a simple pathway that is initiated by Wnt ligand at the cell surface leading, via linear series of interactions between 'core pathway' members, to the induction of nuclear transcription from genes flanked by β-catenin/TCF transcription factor binding sites. Wnt/β-catenin signaling is also regulated by a much larger set of 'non-core regulators'. However the relationship between 'non-core regulators' is currently not well understood. Aberrant activation of the pathway has been shown to drive tumorgenesis in a number of different tissues.MethodsMammalian cells engineered to have a partially-active level of Wnt/β-catenin signaling were screened by transfection for proteins that up or down-regulated a mid-level of TCF-dependent transcription induced by transient expression of an activated LRP6 Wnt co-receptor (∆NLRP).Results141 novel regulators of TCF-dependent transcription were identified. Surprisingly, when tested without ∆NLRP activation, most up-regulators failed to alter TCF-dependent transcription. However, when expressed in pairs, 27 % (466/1170) functionally interacted to alter levels of TCF-dependent transcription. When proteins were displayed as nodes connected by their ability to co-operate in the regulation of TCF-dependent transcription, a network of functional interactions was revealed. In this network, 'core pathway' components (Eg. β-catenin, GSK-3, Dsh) were found to be the most highly connected nodes. Activation of different nodes in this network impacted on the sensitivity to Wnt pathway small molecule antagonists.ConclusionsThe 'functional connectome' identified here strongly supports an alternative model of the Wnt pathway as a complex context-dependent network. The network further suggests that mutational activation of highly connected Wnt signaling nodes predisposed cells to further context-dependent alterations in levels of TCF-dependent transcription that may be important during tumor progression and treatment.

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Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription.

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