scholarly journals GLI1/GLI2 functional interplay is required to control Hedgehog/GLI targets gene expression

2020 ◽  
Vol 477 (17) ◽  
pp. 3131-3145 ◽  
Author(s):  
Ezequiel J. Tolosa ◽  
Maite G. Fernandez-Barrena ◽  
Eriko Iguchi ◽  
Angela L. McCleary-Wheeler ◽  
Ryan M. Carr ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Chromatin Immunoprecipitation ◽  
Target Genes ◽  
Large Set ◽  
Gli Proteins ◽  
Pancreatic Cancer Cells ◽  
Mechanistic Insight ◽  
Mapping Analysis ◽  
First Time ◽  
Insight Into

The Hedgehog-regulated transcription factors GLI1 and GLI2 play overlapping roles in development and disease; however, the mechanisms underlying their interplay remain elusive. We report for the first time that GLI1 and GLI2 physically and functionally interact in cancer cells. GLI1 and GLI2 were shown to co-immunoprecipitate in PANC1 pancreatic cancer cells and RMS13 rhabdomyosarcoma cells. Mapping analysis demonstrated that the zinc finger domains of both proteins are required for their heteromerization. RNAi knockdown of either GLI1 or GLI2 inhibited expression of many well-characterized GLI target genes (BCL2, MYCN, PTCH2, IL7 and CCND1) in PANC1 cells, whereas PTCH1 expression was only inhibited by GLI1 depletion. qPCR screening of a large set of putative canonical and non-canonical Hedgehog/GLI targets identified further genes (e.g. E2F1, BMP1, CDK2) strongly down-regulated by GLI1 and/or GLI2 depletion in PANC1 cells, and demonstrated that ANO1, AQP1 and SOCS1 are up-regulated by knockdown of either GLI1 or GLI2. Chromatin immunoprecipitation showed that GLI1 and GLI2 occupied the same regions at the BCL2, MYCN and CCND1 promoters. Furthermore, depletion of GLI1 inhibited GLI2 occupancy at these promoters, suggesting that GLI1/GLI2 interaction is required for the recruitment of GLI2 to these sites. Together, these findings indicate that GLI1 and GLI2 co-ordinately regulate the transcription of some genes, and provide mechanistic insight into the roles of GLI proteins in carcinogenesis.

scholarly journals Histone H3K23-specific acetylation by MORF is coupled to H3K14 acylation

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Brianna J. Klein ◽  
Suk Min Jang ◽  
Catherine Lachance ◽  
Wenyi Mi ◽  
Jie Lyu ◽  
...  
Keyword(s):  
Posttranslational Modification ◽  
Memory Impairment ◽  
Target Genes ◽  
Epigenetic Mark ◽  
Mechanistic Insight ◽  
Genomic Analyses ◽  
Insight Into

Abstract Acetylation of histone H3K23 has emerged as an essential posttranslational modification associated with cancer and learning and memory impairment, yet our understanding of this epigenetic mark remains insufficient. Here, we identify the native MORF complex as a histone H3K23-specific acetyltransferase and elucidate its mechanism of action. The acetyltransferase function of the catalytic MORF subunit is positively regulated by the DPF domain of MORF (MORFDPF). The crystal structure of MORFDPF in complex with crotonylated H3K14 peptide provides mechanistic insight into selectivity of this epigenetic reader and its ability to recognize both histone and DNA. ChIP data reveal the role of MORFDPF in MORF-dependent H3K23 acetylation of target genes. Mass spectrometry, biochemical and genomic analyses show co-existence of the H3K23ac and H3K14ac modifications in vitro and co-occupancy of the MORF complex, H3K23ac, and H3K14ac at specific loci in vivo. Our findings suggest a model in which interaction of MORFDPF with acylated H3K14 promotes acetylation of H3K23 by the native MORF complex to activate transcription.

scholarly journals Small GTPase Rab21 regulates cell adhesion and controls endosomal traffic of β1-integrins

2006 ◽  
Vol 173 (5) ◽  
pp. 767-780 ◽  
Author(s):  
Teijo Pellinen ◽  
Antti Arjonen ◽  
Karoliina Vuoriluoto ◽  
Katja Kallio ◽  
Jack A.M. Fransen ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cell Adhesion ◽  
Small Gtpases ◽  
Small Gtpase ◽  
Rab Proteins ◽  
Mechanistic Insight ◽  
Cancer Cell Adhesion ◽  
Intracellular Compartments ◽  
First Time ◽  
Insight Into

Dynamic turnover of integrin cell adhesion molecules to and from the cell surface is central to cell migration. We report for the first time an association between integrins and Rab proteins, which are small GTPases involved in the traffic of endocytotic vesicles. Rab21 (and Rab5) associate with the cytoplasmic domains of α-integrin chains, and their expression influences the endo/exocytic traffic of integrins. This function of Rab21 is dependent on its GTP/GDP cycle and proper membrane targeting. Knock down of Rab21 impairs integrin-mediated cell adhesion and motility, whereas its overexpression stimulates cell migration and cancer cell adhesion to collagen and human bone. Finally, overexpression of Rab21 fails to induce cell adhesion via an integrin point mutant deficient in Rab21 association. These data provide mechanistic insight into how integrins are targeted to intracellular compartments and how their traffic regulates cell adhesion.

scholarly journals Diminished miRNA activity is associated with aberrant cytoplasmic intron retention in ALS pathogenesis

2021 ◽  
Author(s):  
Marija Petric-Howe ◽  
Hamish Crerar ◽  
Jacob Neeves ◽  
Giulia E. Tyzack ◽  
Rickie Patani ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Target Genes ◽  
Intron Retention ◽  
Spatiotemporal Dynamics ◽  
Expression Level ◽  
Mechanistic Insight ◽  
Selective Increase ◽  
Insight Into

SUMMARYIntron retention (IR) is now recognized as a dominant splicing event during motor neuron (MN) development, however the role and regulation of intron-retaining transcripts (IRTs) localized to the cytoplasm remain particularly understudied. By resolving the spatiotemporal dynamics of IR underlying distinct stages of MN lineage restriction, we identify a cytoplasmic group of IRTs that is not associated with reduced expression of their own genes but instead with an upregulation of predicted target genes of specific miRNAs, the motifs of which are enriched within the intronic sequences of this group. Next, we show that ALS-causing VCP mutations lead to a selective increase in IR of this particular class of introns. This in turn temporally coincides with an increase in the expression level of predicted target genes of these miRNAs, providing a potential mechanistic insight into ALS pathogenesis. Altogether, we propose a novel role for the cytoplasmic intronic sequences in regulating miRNA activity through miRNA sequestration, which potentially contributes to ALS pathogenesis.

Discovery of a novel human lactate dehydrogenase A (LDHA) inhibitor as an anti-proliferation agent against MIA PaCa-2 pancreatic cancer cells

RSC Advances ◽  
2016 ◽  
Vol 6 (28) ◽  
pp. 23218-23222 ◽  
Author(s):  
Yunpeng Sun ◽  
Chonglin Tao ◽  
Fuxiang Yu ◽  
Wenjun Yang ◽  
Yunfeng Shan ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Lactate Dehydrogenase ◽  
Cancer Cells ◽  
Pancreatic Cancer Cells ◽  
Proliferation Activity ◽  
First Time

A potent LDHA inhibitor with anti-proliferation activity against MIA PaCa-2 cancer cells was first time reported.

scholarly journals An explainable artificial intelligence approach for decoding the enhancer histone modifications code and identification of novel enhancers in Drosophila

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Jareth C. Wolfe ◽  
Liudmila A. Mikheeva ◽  
Hani Hagras ◽  
Nicolae Radu Zabet
Keyword(s):  
Artificial Intelligence ◽  
Histone Modifications ◽  
Target Genes ◽  
Large Set ◽  
Coding Regions ◽  
Explainable Artificial Intelligence ◽  
High Degree ◽  
Intelligence Approach ◽  
Artificial Intelligence Approach ◽  
Insight Into

Abstract Background Enhancers are non-coding regions of the genome that control the activity of target genes. Recent efforts to identify active enhancers experimentally and in silico have proven effective. While these tools can predict the locations of enhancers with a high degree of accuracy, the mechanisms underpinning the activity of enhancers are often unclear. Results Using machine learning (ML) and a rule-based explainable artificial intelligence (XAI) model, we demonstrate that we can predict the location of known enhancers in Drosophila with a high degree of accuracy. Most importantly, we use the rules of the XAI model to provide insight into the underlying combinatorial histone modifications code of enhancers. In addition, we identified a large set of putative enhancers that display the same epigenetic signature as enhancers identified experimentally. These putative enhancers are enriched in nascent transcription, divergent transcription and have 3D contacts with promoters of transcribed genes. However, they display only intermediary enrichment of mediator and cohesin complexes compared to previously characterised active enhancers. We also found that 10–15% of the predicted enhancers display similar characteristics to super enhancers observed in other species. Conclusions Here, we applied an explainable AI model to predict enhancers with high accuracy. Most importantly, we identified that different combinations of epigenetic marks characterise different groups of enhancers. Finally, we discovered a large set of putative enhancers which display similar characteristics with previously characterised active enhancers.

scholarly journals Lycopene Inhibits Reactive Oxygen Species-Mediated NF-κB Signaling and Induces Apoptosis in Pancreatic Cancer Cells

Nutrients ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 762 ◽  
Author(s):  
Yoonseon Jeong ◽  
Joo Lim ◽  
Hyeyoung Kim
Keyword(s):  
Reactive Oxygen Species ◽  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Target Genes ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Pancreatic Cancer Cells ◽  
Mitochondrial Ros ◽  
Apoptotic Effect ◽  
Survival Signaling

Generation of excess quantities of reactive oxygen species (ROS) caused by mitochondrial dysfunction facilitates rapid growth of pancreatic cancer cells. Elevated ROS levels in cancer cells cause an anti-apoptotic effect by activating survival signaling pathways, such as NF-κB and its target gene expression. Lycopene, a carotenoid found in tomatoes and a potent antioxidant, displays a protective effect against pancreatic cancer. The present study was designed to determine if lycopene induces apoptosis of pancreatic cancer PANC-1 cells by decreasing intracellular and mitochondrial ROS levels, and consequently suppressing NF-κB activation and expression of NF-κB target genes including cIAP1, cIAP2, and survivin. The results show that the lycopene decreased intracellular and mitochondrial ROS levels, mitochondrial function (determined by the mitochondrial membrane potential and oxygen consumption rate), NF-κB activity, and expression of NF-κB-dependent survival genes in PANC-1 cells. Lycopene reduced cell viability with increases in active caspase-3 and the Bax to Bcl-2 ratio in PANC-1 cells. These findings suggest that supplementation of lycopene could potentially reduce the incidence of pancreatic cancer.

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