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#33608451   2021/02/19 To Up

Colorectal cancer-associated Smad4 R361 hotspot mutations boost Wnt/β-catenin signaling through enhanced Smad4-LEF1 binding.

10-30% of colorectal cancer (CRC) patients harbor either loss of or missense mutations in SMAD4, a critical component of the TGFβ signaling pathway. The pathophysiological function of missense mutations in Smad4 is not fully understood. They usually map to the MH2 domain, specifically to residues that are involved in heterodimeric complex formation with regulatory Smads (such as Smad2/3) and ensuing transcriptional activation. These detrimental effects suggest that SMAD4 missense mutations can be categorized as loss-of-function. However, they tend to cluster in a few hotspots, which is more consistent with them acting by a gain-of-function mechanism. In this study, we investigated the functional role of Smad4 R361 mutants by re-expressing two R361 Smad4 variants in several Smad4-null CRC cell lines. As predicted, R361 mutations disrupted Smad2/3-Smad4 heteromeric complex formation and abolished canonical TGFβ signaling. In that, they were similar to SMAD4 loss. However, RNA sequencing and subsequent RT-PCR revealed that Smad4mut cells acquired a gene signature associated with enhanced Lef1 protein function and increased Wnt signaling. Mechanistically, Smad4 mutant proteins retained binding to Lef1 protein and drove a commensurate increase in downstream Wnt signaling as measured by TOP/FOP luciferase assay and Wnt-dependent cell motility. Consistent with these findings, human CRCs with SMAD4 missense mutations were less likely to acquire activating mutations in the key Wnt pathway gene CTNNB1 (encoding beta catenin) than CRCs with truncating SMAD4 nonsense mutations. Implications: Our studies suggest that in CRC hotspot mutations in Smad4 confer enhanced Wnt signaling and possibly heightened sensitivity to Wnt pathway inhibitors.
Claudia B Lanauze, Priyanka Sehgal, Katharina Hayer, Manuel Torres-Diz, James A Pippin, Struan F A Grant, Andrei Thomas-Tikhonenko

2159 related Products with: Colorectal cancer-associated Smad4 R361 hotspot mutations boost Wnt/β-catenin signaling through enhanced Smad4-LEF1 binding.

10100 µg50 ug50 ug96T50 ug1mg50 ug1 SetEach

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#33587034   2021/02/15 To Up

A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells.

The canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR99021 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs are independent of direct engagement of TCF/LEF/β-catenin transcriptional complexes at low CHIR-dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter-enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin's direct transcriptional role is restricted to the induction of NPCs, where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.
Qiuyu Guo, Albert Kim, Bin Li, Andrew Ransick, Helena Bugacov, Xi Chen, Nils Lindström, Aaron Brown, Leif Oxburgh, Bing Ren, Andrew P McMahon

1637 related Products with: A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells.

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#33539420   2021/02/04 To Up

CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3.

Circular RNAs (circRNAs) are novel single-stranded noncoding RNAs that can decoy other RNAs to inhibit their functions. Kaposi's sarcoma (KS), caused by oncogenic Kaposi's sarcoma-associated herpesvirus (KSHV), is a highly angiogenic and invasive vascular tumor of endothelial origin commonly found in AIDS patients. We have recently shown that KSHV-encoded viral interferon regulatory factor 1 (vIRF1) induces cell invasion, angiogenesis and cellular transformation; however, the role of circRNAs is largely unknown in the context of KSHV vIRF1. Herein, transcriptome analysis identified 22 differentially expressed cellular circRNAs regulated by vIRF1 in an endothelial cell line. Among them, circARFGEF1 was the highest upregulated circRNA. Mechanistically, vIRF1 induced circARFGEF1 transcription by binding to transcription factor lymphoid enhancer binding factor 1 (Lef1). Importantly, upregulation of circARFGEF1 was required for vIRF1-induced cell motility, proliferation and in vivo angiogenesis. circARFGEF1 functioned as a competing endogenous RNAs (ceRNAs) by binding to and inducing degradation of miR-125a-3p. Mass spectrometry analysis demonstrated that glutaredoxin 3 (GLRX3) was a direct target of miR-125a-3p. Knockdown of GLRX3 impaired cell motility, proliferation and angiogenesis induced by vIRF1. Taken together, vIRF1 transcriptionally activates circARFGEF1, potentially by binding to Lef1, to promote cell oncogenic phenotypes via inhibiting miR-125a-3p and inducing GLRX3. These findings define a novel mechanism responsible for vIRF1-induced oncogenesis and establish the scientific basis for targeting these molecules for treating KSHV-associated cancers.
Shuihong Yao, Xuemei Jia, Fei Wang, Liuxue Sheng, Pengxia Song, Yanhui Cao, Hongjuan Shi, Weifei Fan, Xiangya Ding, Shou-Jiang Gao, Chun Lu

2740 related Products with: CircRNA ARFGEF1 functions as a ceRNA to promote oncogenic KSHV-encoded viral interferon regulatory factor induction of cell invasion and angiogenesis by upregulating glutaredoxin 3.

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#33523480   2021/02/01 To Up

Human fibroblast-derived extracellular vesicles promote hair growth in cultured human hair follicles.

Hair loss is a prevalent medical condition affecting both genders. In this study, we investigate the effects of a specific class of extracellular vesicles (EVs), namely human normal fibroblast-derived EVs (hFB-EVs), on human dermal papilla (DP) and outer root sheath (ORS) cells and examine the molecular mechanisms responsible for hair growth in hair follicles (HFs). We find that Wnt3a, which maintains the hair-generating activity of DP cells, is enriched and more strongly associated with hFB-EVs than with fibroblasts. Furthermore, hFB-EV-associated Wnt3a mediated receptor activation in cultured DP cells, leading to an increase in β-catenin in the cytoplasm and its translocation into the nucleus, thereby elevating expression of the target genes Axin2 and Lef1. Additionally, hFB-EVs promoted the migration, proliferation, and differentiation of ORS cells and elongation of the hair shaft in human HFs. These findings revealed a novel mechanism by which hFB-EVs influence hair growth.
Ramya Lakshmi Rajendran, Prakash Gangadaran, Mi Hee Kwack, Ji Min Oh, Chae Moon Hong, Young Kwan Sung, Jaetae Lee, Byeong-Cheol Ahn

2882 related Products with: Human fibroblast-derived extracellular vesicles promote hair growth in cultured human hair follicles.

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#33456719   2020/12/24 To Up

Suppressive effects of valproic acid on caudal fin regeneration in adult zebrafish.

Zebrafish can regenerate fins following injury through an epimorphic process that includes the formation of new tissues and reconstruction of the original morphology. In this study, the effects of valproic acid (VPA), a widely used anti-epileptic drug, on fin regeneration were studied after the caudal fin amputation of adult zebrafish. In the control group, zebrafish formed new tissues and reconstructed the original rays 14 days after amputation (dpa). Meanwhile, VPA treatments between 20 and 200 µM following amputation suppressed fin regeneration in a dose-dependent manner and altered morphological characteristics, such as bifurcation and segmentation, in the rays. Compared to the control, VPA also delayed blastema formation and decreased cell proliferation in the mesenchymal area of the regenerated fin. The mRNA expression of a downstream signaling gene in the Wnt pathway, was transiently increased in the regenerated fin of the control at 2 dpa; the same increase was not observed in the VPA-treated zebrafish. Sodium butyrate (SB), an histone deacetylase activity (HDAC) inhibitor, suppressed the fin regeneration without affecting the morphological characteristics of the regenerated ray. Furthermore, the transient increase of mRNA was not suppressed in the SB-treated zebrafish. These results suggested that VPA's suppressive effects on fin regeneration are partly mediated through decreased cell proliferation and mRNA expression.
Yunkyoung Lee, Dohee Kim, Chang-Joong Lee

1513 related Products with: Suppressive effects of valproic acid on caudal fin regeneration in adult zebrafish.

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#33431799   2021/01/11 To Up

CHIP promotes Wnt signaling and regulates Arc stability by recruiting and polyubiquitinating LEF1 or Arc.

The carboxyl terminus of Hsc70-interacting protein (CHIP), an E3 ubiquitin ligase, participates in many cellular processes such as protein degradation, trafficking, autophagy, apoptosis, and multiple signaling transductions. The mutant of CHIP (p.T246M) causes the spinocerebellar autosomal recessive 16 (SCAR16), a neurodegenerative disease characterized by spinocerebellar atrophy. Previous studies have shown that Wnt signaling and activity-regulated cytoskeleton-associated protein (Arc) play important roles in neurodegenerative diseases. However, the mechanisms by which CHIP regulates Wnt signaling and the stability of Arc that may affect SCAR16 are still unclear. We show that overexpression of CHIP promoted the activation of Wnt signaling, and enhanced the interaction between LEF1 and β-catenin through heightening the K63-linked polyubiquitin chains attached to LEF1, while the knockdown of CHIP had the opposite effect. Moreover, we verified that Wnt signaling was inhibited in the rat models of SCAR16 induced by the CHIP (p.T246M) mutant. CHIP also accelerated the degradation of Arc and regulated the interaction between Arc and GSK3β by heightening the K48- or K63-linked polyubiquitin chains, which further potentiated the interaction between GSK3β and β-catenin. Our data identify that CHIP is an undescribed regulator of Wnt signaling and Arc stability which may be related to the occurrence of SCAR16.
Yuchun Liu, Yao Sun, Yonghui Huang, Kang Cheng, Yuming Xu, Qingnan Tian, Shoutao Zhang

2150 related Products with: CHIP promotes Wnt signaling and regulates Arc stability by recruiting and polyubiquitinating LEF1 or Arc.

100 mg100ug100ug200 25 mg 25 MG100ug10 mg 5 G1000 TESTS/0.65ml

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