Wnt some lose some: transcriptional governance of stem cells by Wnt/β-catenin signaling

Abstract

In mammals, Wnt/b-catenin signaling features prominently in stem cells and cancers, but how and for what purposes have been matters of much debate. In this review, we summarize our current knowledge of Wnt/b-catenin signaling and its downstream transcriptional regulators in normal and malignant stem cells. We centered this review largely on three types of stem cells-embryonic stem cells, hair follicle stem cells, and intestinal epithelial stem cells-in which the roles of Wnt/b-catenin have been extensively studied. Using these models, we unravel how many controversial issues surrounding Wnt signaling have been resolved by dissecting the diversity of its downstream circuitry and effectors, often leading to opposite outcomes of Wnt/b-catenin-mediated regulation and differences rooted in stage-and context-dependent effects.

Regulation of the TMEPAI promoter by TCF7L2: the C-terminal tail of TCF7L2 is essential to activate theTMEPAIgene

“…Gal4 DBD-C-clamp and Gal4 DBD-C-clamp(C463A) were constructed by fusion of Gal4-DBD with TCF7L2 (from Q 411 to E 596 ) or TCF7L2(C463A) (from Q 411 to E 596 ), respectively. consistent with notion that the N-terminal domain of TCF/LEF family members plays an important role in the activation of canonical Wnt target genes via its association with b-catenin which recruits CBP/ p300 (5).…”

“…The canonical pathway is mediated by b-catenin, which can interact with T-cell factor (TCF)/lymphoid enhance factor (LEF) family members in the nucleus, where the complex between b-catenin and TCF/LEF family members regulates Wnt target genes. On the other hand, the non-canonical pathway, which is alternatively termed the b-catenin-independent Wnt signalling pathway, triggers calcium efflux, ROCK activation, JNK phosphorylation to control cytoskeleton rearrangement, planar cell polarity and transcriptional events (5). The TCF/LEF family, encompasses TCF7 (also termed TCF1), TCF7L1 (also termed TCF3), TCF7L2 (also termed TCF4) and LEF1 (also termed TCF7L3) in mammals.…”

“…There are four conserved regions in all TCF/LEFs: the b-catenin binding region in the N terminus, the high-mobility group (HMG) box in the middle region, the basic tail close to the HMG box and the nuclear localization signal (NLS). The HMG box recognizes a specific DNA sequence, (C/G)TTT(C/G)(A/T)N(C/G), together with the basic tail to regulate Wnt/b-catenin target genes (1,3,5). Besides, some isoforms of the TCF/LEF family include the C-clamp in the C-terminal tail, which is known to act as the secondary DNA-binding domain (DBD).…”

“…In addition, the C-clamp in the splicing variants of TCF7 and TCF7L2 acts as the secondary DNA-binding region that preferentially recognizes GC-rich sequences (1,5). Since TCF7L2 is known to bind to TGF-b-responsive TCF7L2-binding element (TTE) within the enhancer of the TMEPAI gene in TGF-b-induced TMEPAI activation, TTE is a critical cis-element for TGF-b to potentiate the transcription of TMEPAI together with Smad3 (10).…”

Transcription Factor PAX6 (Paired Box 6) Controls Limbal Stem Cell Lineage in Development and Disease

“…This analysis identified numerous GO terms and signaling pathways affecting many cellular and metabolic processes (data not shown). In particular, however, the Notch, Wnt, and TGF-␤ pathways emerged as important from this analysis, consistent with their critical roles in the self-renewal and lineage commitment of stem cells from a variety of tissues (21)(22)(23), including the epithelium. Graphical representation of expression changes for distinct members of these pathways is provided in Fig.…”