scholarly journals DIPA-family coiled-coils bind conserved isoform-specific head domain of p120-catenin family: potential roles in hydrocephalus and heterotopia

2014 ◽  
Vol 25 (17) ◽  
pp. 2592-2603 ◽  
Author(s):  
Nicholas O. Markham ◽  
Caleb A. Doll ◽  
Michael R. Dohn ◽  
Rachel K. Miller ◽  
Huapeng Yu ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Specific Binding ◽  
Protein A ◽  
Family Members ◽  
Adherens Junction ◽  
Dependent Manner ◽  
Interacting Protein ◽  
P120 Catenin ◽  
Mesenchymal Transition ◽  
Head Domain

p120-catenin (p120) modulates adherens junction (AJ) dynamics by controlling the stability of classical cadherins. Among all p120 isoforms, p120-3A and p120-1A are the most prevalent. Both stabilize cadherins, but p120-3A is preferred in epithelia, whereas p120-1A takes precedence in neurons, fibroblasts, and macrophages. During epithelial-to-mesenchymal transition, E- to N-cadherin switching coincides with p120-3A to -1A alternative splicing. These isoforms differ by a 101–amino acid “head domain” comprising the p120-1A N-terminus. Although its exact role is unknown, the head domain likely mediates developmental and cancer-associated events linked to p120-1A expression (e.g., motility, invasion, metastasis). Here we identified delta-interacting protein A (DIPA) as the first head domain–specific binding partner and candidate mediator of isoform 1A activity. DIPA colocalizes with AJs in a p120-1A- but not 3A-dependent manner. Moreover, all DIPA family members (Ccdc85a, Ccdc85b/DIPA, and Ccdc85c) interact reciprocally with p120 family members (p120, δ-catenin, p0071, and ARVCF), suggesting significant functional overlap. During zebrafish neural tube development, both knockdown and overexpression of DIPA phenocopy N-cadherin mutations, an effect bearing functional ties to a reported mouse hydrocephalus phenotype associated with Ccdc85c. These studies identify a novel, highly conserved interaction between two protein families that may participate either individually or collectively in N-cadherin–mediated development.

scholarly journals IGF2BP1 is a targetable SRC/MAPK-dependent driver of invasive growth in ovarian cancer

2020 ◽  
Author(s):  
Nadine Bley ◽  
Annekatrin Schott ◽  
Simon Müller ◽  
Danny Misiak ◽  
Marcell Lederer ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Rna Binding ◽  
3D Culture ◽  
Adherens Junction ◽  
Ovarian Cancer Cells ◽  
Invasive Growth ◽  
Dependent Manner ◽  
Mesenchymal Transition

AbstractEpithelial-to-mesenchymal transition (EMT) is a hallmark of aggressive, mesenchymal-like high-grade serous ovarian carcinoma (HG-SOC). The SRC kinase is a key driver of cancer-associated EMT promoting adherens junction (AJ) disassembly by phosphorylation-driven internalization and degradation of AJ proteins. Here we show, that the IGF2 mRNA binding protein 1 (IGF2BP1) is up-regulated in mesenchymal-like HG-SOC and promotes SRC activation by a previously unknown protein-ligand-induced, but RNA-independent mechanism. IGF2BP1-driven invasive growth of ovarian cancer cells essentially relies on the SRC-dependent disassembly of AJs. Concomitantly, IGF2BP1 enhances ERK2 expression in a RNA-binding dependent manner. Together this reveals a post-transcriptional mechanism of interconnected stimulation of SRC/ERK signaling in ovarian cancer cells. The IGF2BP1-SRC/ERK2 axis is targetable by the SRC-inhibitor saracatinib and MEK-inhibitor selumetinib. However, due to IGF2BP1-directed stimulation only combinatorial treatment effectively overcomes the IGF2BP1-promoted invasive growth in 3D culture conditions as well as intraperitoneal mouse models. In conclusion, we reveal an unexpected role of IGF2BP1 in enhancing SRC/MAPK-driven invasive growth of ovarian cancer cells. This provides a rational for the therapeutic benefit of combinatorial SRC/MEK inhibition in mesenchymal-like HG-SOC.Graphical Abstract

scholarly journals Pyrvinium pamoate inhibits cell proliferation through ROS-mediated AKT-dependent signaling pathway in colorectal cancer

2021 ◽  
Vol 38 (2) ◽  
Author(s):  
Wenqian Zheng ◽  
Jinhui Hu ◽  
Yiming Lv ◽  
Bingjun Bai ◽  
Lina Shan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Epithelial To Mesenchymal Transition ◽  
Flow Cytometric Analysis ◽  
Inhibitory Effect ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Dependent Signaling Pathway ◽  
Pyrvinium Pamoate

AbstractThe use of the anthelmintic drug pyrvinium pamoate (PP) in cancer therapy has been extensively investigated in the last decade. PP has been shown to have an inhibitory effect in colorectal cancer (CRC), but the underlying mechanism remains elusive. We aimed to investigate the antitumor activity and mechanisms of PP in CRC. In the present study, we used CCK-8 assays, colony formation assays, and western blotting to reveal that PP effectively suppressed CRC cell proliferation and the AKT-dependent signaling pathway in a concentration-dependent and time-dependent manner. Flow cytometric analysis and fluorescence microscopy demonstrated that PP increased intracellular reactive oxygen species (ROS) accumulation. We found that the inhibitory effect of PP on cell proliferation and AKT protein expression induced by PP could be partially reversed by N-acetyl-l-cysteine (NAC), an ROS scavenger. In addition, the results also demonstrated that PP inhibited cell migration by modulating epithelial-to-mesenchymal transition (EMT)-related proteins, including E-cadherin and vimentin. In conclusion, our data suggested that PP effectively inhibited cell proliferation through the ROS-mediated AKT-dependent signaling pathway in CRC, further providing evidence for the use of PP as an antitumor agent.

scholarly journals IKBIP is a novel EMT-related biomarker and predicts poor survival in glioma

2021 ◽  
Vol 12 (1) ◽  
pp. 009-019
Author(s):  
Ying Yang ◽  
Jin Wang ◽  
Shihai Xu ◽  
Wen Lv ◽  
Fei Shi ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Molecular Subtype ◽  
Enrichment Analysis ◽  
Gene Set Enrichment Analysis ◽  
Transcriptional Level ◽  
Who Grade ◽  
Interacting Protein ◽  
Mesenchymal Transition ◽  
Gene Set ◽  
Substrate Adhesion

Abstract Background In cancer, kappa B-interacting protein (IKBIP) has rarely been reported. This study aimed at investigating its expression pattern and biological function in brain glioma at the transcriptional level. Methods We selected 301 glioma patients with microarray data from CGGA database and 697 glioma patients with RNAseq data from TCGA database. Transcriptional data and clinical data of 998 samples were analyzed. Statistical analysis and figure generating were performed with R language. Results We found that IKBIP expression showed positive correlation with WHO grade of glioma. IKBIP was increased in isocitrate dehydrogenase (IDH) wild type and mesenchymal molecular subtype of glioma. Gene ontology analysis demonstrated that IKBIP was profoundly associated with extracellular matrix organization, cell–substrate adhesion and response to wounding in both pan-glioma and glioblastoma. Subsequent gene set enrichment analysis revealed that IKBIP was particularly correlated with epithelial-to-mesenchymal transition (EMT). To further elucidate the relationship between IKBIP and EMT, we performed gene set variation analysis to screen the EMT-related signaling pathways and found that IKBIP expression was significantly associated with PI3K/AKT, hypoxia and TGF-β pathway. Moreover, IKBIP expression was found to be synergistic with key biomarkers of EMT, especially with N-cadherin, vimentin, snail, slug and TWIST1. Finally, higher IKBIP indicated significantly shorter survival for glioma patients. Conclusions IKBIP was associated with more aggressive phenotypes of gliomas. Furthermore, IKBIP was significantly involved in EMT and could serve as an independent prognosticator in glioma.

scholarly journals Phosphorylation of Rab11-FIP2 regulates polarity in MDCK cells

2012 ◽  
Vol 23 (12) ◽  
pp. 2302-2318 ◽  
Author(s):  
Lynne A. Lapierre ◽  
Kenya M. Avant ◽  
Cathy M. Caldwell ◽  
Asli Oztan ◽  
Gerard Apodaca ◽  
...  
Keyword(s):  
Tight Junctions ◽  
Mdck Cell ◽  
Mdck Cells ◽  
Adherens Junction ◽  
Cellular Polarity ◽  
Interacting Protein ◽  
P120 Catenin ◽  
Myosin Vb ◽  
Darby Canine Kidney

The Rab11 effector Rab11-family interacting protein 2 (Rab11-FIP2) regulates transcytosis through its interactions with Rab11a and myosin Vb. Previous studies implicated Rab11-FIP2 in the establishment of polarity in Madin–Darby canine kidney (MDCK) cells through phosphorylation of Ser-227 by MARK2. Here we examine the dynamic role of Rab11-FIP2 phosphorylation on MDCK cell polarity. Endogenous Rab11-FIP2 phosphorylated on Ser-227 coalesces on vesicular plaques during the reestablishment of polarity after either monolayer wounding or calcium switch. Whereas expression of the nonphosphorylatable Rab11-FIP2(S227A) elicits a loss in lumen formation in MDCK cell cysts grown in Matrigel, the putative pseudophosphorylated Rab11-FIP2(S227E) mutant induces the formation of cysts with multiple lumens. On permeable filters, Rab11-FIP2(S227E)–expressing cells exhibit alterations in the composition of both the adherens and tight junctions. At the adherens junction, p120 catenin and K-cadherin are retained, whereas the majority of the E-cadherin is lost. Although ZO-1 is retained at the tight junction, occludin is lost and the claudin composition is altered. Of interest, the effects of Rab11-FIP2 on cellular polarity did not involve myosin Vb or Rab11a. These results indicate that Ser-227 phosphorylation of Rab11-FIP2 regulates the composition of both adherens and tight junctions and is intimately involved in the regulation of polarity in epithelial cells.

scholarly journals Cutaneous Epithelial to Mesenchymal Transition Activator ZEB1 Regulates Wound Angiogenesis and Closure in a Glycemic Status–Dependent Manner

Diabetes ◽  
2019 ◽  
Vol 68 (11) ◽  
pp. 2175-2190 ◽  
Author(s):  
Kanhaiya Singh ◽  
Mithun Sinha ◽  
Durba Pal ◽  
Saba Tabasum ◽  
Surya C. Gnyawali ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Dependent Manner ◽  
Glycemic Status ◽  
Mesenchymal Transition

Heptachlor-induced epithelial to mesenchymal transition in HK-2 cells mediated via TGF-β1/Smad signalling

2019 ◽  
Vol 38 (5) ◽  
pp. 567-577 ◽  
Author(s):  
N Singh ◽  
M Siddarth ◽  
R Ghosh ◽  
AK Tripathi ◽  
BD Banerjee
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Dependent Manner ◽  
Mesenchymal Transition ◽  
Epithelial Marker ◽  
Proximal Tubular ◽  
Renal Proximal Tubular ◽  
Smad 3 ◽  
Tgf Β1

This study investigated the effect of heptachlor-induced oxidative stress (OS) on transforming growth factor (TGF)-β1-mediated epithelial to mesenchymal transition (EMT) in human renal proximal tubular epithelial (HK-2) cells. Following treatment of HK-2 cells with an increasing concentration of heptachlor (0.01–10 µM) for 24 h, the intracellular reactive oxygen species and malondialdehyde level increased, whereas the glutathione-s-hydroxylase (GSH) level declined significantly in a dose-dependent manner. Pretreatment with N-acetyl cysteine attenuates the heptachlor-induced OS. In this study, we have shown that heptachlor-induced OS regulates the mRNA expression of TGF-β1-mediated Smad signalling genes accompanied by increased nuclear localization of phosphorylated Smad-2 and phosphorylated Smad-3. Furthermore, the m-RNA and protein level of epithelial marker, that is, E-cadherin decreased while the mesenchymal marker, that is, α-smooth muscle actin increased in heptachlor exposed HK-2 cells. In conclusion, heptachlor-induced OS might be responsible for the activation of TGF-β1/Smad signalling which ultimately leads to renal damage by means of EMT.

scholarly journals Regulation of the Mechanism ofTWIST1Transcription by BHLHE40 and BHLHE41 in Cancer Cells

2015 ◽  
Vol 35 (24) ◽  
pp. 4096-4109 ◽  
Author(s):  
Kazuo Asanoma ◽  
Ge Liu ◽  
Takako Yamane ◽  
Yoko Miyanari ◽  
Tomoka Takao ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Invasion ◽  
Transcriptional Activity ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Cell Invasion ◽  
Dependent Manner ◽  
Promoter Regions ◽  
Mesenchymal Transition ◽  
Basal Transcriptional Activity

BHLHE40 and BHLHE41 (BHLHE40/41) are basic helix-loop-helix type transcription factors that play key roles in multiple cell behaviors. BHLHE40/41 were recently shown to be involved in an epithelial-to-mesenchymal transition (EMT). However, the precise mechanism of EMT control by BHLHE40/41 remains unclear. In the present study, we demonstrated that BHLHE40/41 expression was controlled in a pathological stage-dependent manner in human endometrial cancer (HEC). Ourin vitroassays showed that BHLHE40/41 suppressed tumor cell invasion. BHLHE40/41 also suppressed the transcription of the EMT effectorsSNAI1,SNAI2, andTWIST1. We identified the critical promoter regions ofTWIST1for its basal transcriptional activity. We elucidated that the transcription factor SP1 was involved in the basal transcriptional activity ofTWIST1and that BHLHE40/41 competed with SP1 for DNA binding to regulate gene transcription. This study is the first to report the detailed functions of BHLHE40 and BHLHE41 in the suppression of EMT effectorsin vitro. Our results suggest that BHLHE40/41 suppress tumor cell invasion by inhibiting EMT in tumor cells. We propose that BHLHE40/41 are promising markers to predict the aggressiveness of each HEC case and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate HEC progression.

scholarly journals Bnip3 and AIF cooperate to induce apoptosis and cavitation during epithelial morphogenesis

2012 ◽  
Vol 198 (1) ◽  
pp. 103-114 ◽  
Author(s):  
Yanmei Qi ◽  
Xiaoxiang Tian ◽  
Jie Liu ◽  
Yaling Han ◽  
Alan M. Graham ◽  
...  
Keyword(s):  
Protein A ◽  
Hypoxia Inducible Factor ◽  
Embryonic Stem ◽  
Embryoid Bodies ◽  
Epithelial Morphogenesis ◽  
Dependent Manner ◽  
Interacting Protein ◽  
The Core ◽  
Adenovirus E1b ◽  
Induced Apoptosis

Apoptosis is an essential step in cavitation during embryonic epithelial morphogenesis, but its mechanisms are largely unknown. In this paper, we used embryonic stem cell–differentiated embryoid bodies (EBs) as a model and found that Bnip3 (Bcl-2/adenovirus E1B 19-kD interacting protein), a BH3-only proapoptotic protein, was highly up-regulated during cavitation in a hypoxia-dependent manner. Short hairpin RNA silencing of Bnip3 inhibited apoptosis of the core cells and delayed cavitation. We show that the Bnip3 up-regulation was mediated mainly by hypoxia-inducible factor (HIF)–2. Ablation of HIF-2α or HIF-1β, the common β subunit of HIF-1 and -2, suppressed Bnip3 up-regulation and inhibited apoptosis and cavitation. We further show that apoptosis-inducing factor (AIF) cooperated with Bnip3 to promote lumen clearance. Bnip3 silencing in AIF-null EBs nearly blocked apoptosis and cavitation. Moreover, AIF also regulated Bnip3 expression through mitochondrial production of reactive oxygen species and consequent HIF-2α stabilization. These results uncover a mechanism of cavitation through hypoxia-induced apoptosis of the core cells mediated by HIFs, Bnip3, and AIF.

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