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Article ; Online: NACK and INTEGRATOR act coordinately to activate Notch-mediated transcription in tumorigenesis

Elena Shersher / Mohini Lahiry / Annamil Alvarez-Trotta / Giulia Diluvio / David J. Robbins / Ramin Shiekhattar / Anthony J. Capobianco

Cell Communication and Signaling, Vol 19, Iss 1, Pp 1-

2021 Volume 12

Abstract: Abstract Background Notch signaling drives many aspects of neoplastic phenotype. Here, we report that the Integrator complex (INT) is a new component of the Notch transcriptional supercomplex. Together with Notch Activation Complex Kinase (NACK), INT ... ...

Abstract	Abstract Background Notch signaling drives many aspects of neoplastic phenotype. Here, we report that the Integrator complex (INT) is a new component of the Notch transcriptional supercomplex. Together with Notch Activation Complex Kinase (NACK), INT activates Notch1 target genes by driving RNA polymerase II (RNAPII)-dependent transcription, leading to tumorigenesis. Methods Size exclusion chromatography and CBF-1/RBPJ/Suppressor of Hairless/Lag-1 (CSL)-DNA affinity fast protein liquid chromatography (FPLC) was used to purify Notch/CSL-dependent complexes for liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Chromatin immunoprecipitation (ChIP) and quantitative polymerase chain reaction (qPCR) were performed to investigate transcriptional regulation of Notch target genes. Transfection of Notch Ternary Complex components into HEK293T cells was used as a recapitulation assay to study Notch-mediated transcriptional mechanisms. Gene knockdown was achieved via RNA interference and the effects of protein depletion on esophageal adenocarcinoma (EAC) proliferation were determined via a colony formation assay and murine xenografts. Western blotting was used to examine expression of INT subunits in EAC cells and evaluate apoptotic proteins upon INT subunit 11 knockdown (INTS11 KD). Gene KD effects were further explored via flow cytometry. Results We identified the INT complex as part of the Notch transcriptional supercomplex. INT, together with NACK, activates Notch-mediated transcription. While NACK is required for the recruitment of RNAPII to a Notch-dependent promoter, the INT complex is essential for RNAPII phosphorylated at serine 5 (RNAPII-S5P), leading to transcriptional activation. Furthermore, INT subunits are overexpressed in EAC cells and INTS11 KD results in G2/M cell cycle arrest, apoptosis, and cell growth arrest in EAC. Conclusions This study identifies the INT complex as a novel co-factor in Notch-mediated transcription that together with NACK activates Notch target genes and leads to ...
Keywords	Notch signaling ; NACK ; Integrator ; Esophageal adenocarcinoma ; Tumorigenesis ; Transcriptional activation ; Medicine ; R ; Cytology ; QH573-671
Subject code	570
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Casein Kinase 1α as a Regulator of Wnt-Driven Cancer

Chen Shen / Anmada Nayak / Ricardo A. Melendez / Daniel T. Wynn / Joshua Jackson / Ethan Lee / Yashi Ahmed / David J. Robbins

International Journal of Molecular Sciences, Vol 21, Iss 5940, p

2020 Volume 5940

Abstract: Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. ...

Abstract	Wnt signaling regulates numerous cellular processes during embryonic development and adult tissue homeostasis. Underscoring this physiological importance, deregulation of the Wnt signaling pathway is associated with many disease states, including cancer. Here, we review pivotal regulatory events in the Wnt signaling pathway that drive cancer growth. We then discuss the roles of the established negative Wnt regulator, casein kinase 1α (CK1α), in Wnt signaling. Although the study of CK1α has been ongoing for several decades, the bulk of such research has focused on how it phosphorylates and regulates its various substrates. We focus here on what is known about the mechanisms controlling CK1α, including its putative regulatory proteins and alternative splicing variants. Finally, we describe the discovery and validation of a family of pharmacological CK1α activators capable of inhibiting Wnt pathway activity. One of the important advantages of CK1α activators, relative to other classes of Wnt inhibitors, is their reduced on-target toxicity, overcoming one of the major impediments to developing a clinically relevant Wnt inhibitor. Therefore, we also discuss mechanisms that regulate CK1α steady-state homeostasis, which may contribute to the deregulation of Wnt pathway activity in cancer and underlie the enhanced therapeutic index of CK1α activators.
Keywords	Wnt ; cancer ; targeted therapies ; CK1α ; kinase agonists ; review ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	570
Language	English
Publishing date	2020-08-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Transcriptome-wide analysis of changes in the fetal placenta associated with prenatal arsenic exposure in the New Hampshire Birth Cohort Study

Emily F. Winterbottom / Yuguang Ban / Xiaodian Sun / Anthony J. Capobianco / Carmen J. Marsit / Xi Chen / Lily Wang / Margaret R. Karagas / David J. Robbins

Environmental Health, Vol 18, Iss 1, Pp 1-

2019 Volume 10

Abstract: Abstract Background Increasing evidence suggests that prenatal exposure to arsenic, even at common environmental levels, adversely affects child health. These adverse effects include impaired fetal growth, which can carry serious health implications ... ...

Abstract	Abstract Background Increasing evidence suggests that prenatal exposure to arsenic, even at common environmental levels, adversely affects child health. These adverse effects include impaired fetal growth, which can carry serious health implications lifelong. However, the mechanisms by which arsenic affects fetal health and development remain unclear. Methods We addressed this question using a group of 46 pregnant women selected from the New Hampshire Birth Cohort Study (NHBCS), a US cohort exposed to low-to-moderate arsenic levels in drinking water through the use of unregulated private wells. Prenatal arsenic exposure was assessed using maternal urine samples taken at mid-gestation. Samples of the fetal portion of the placenta were taken from the base of the umbilical cord insertion at the time of delivery, stored in RNAlater and frozen. We used RNA sequencing to analyze changes in global gene expression in the fetal placenta associated with in utero arsenic exposure, adjusting for maternal age. Gene set enrichment analysis and enrichment mapping were then used to identify biological processes represented by the differentially expressed genes. Since our previous analyses have identified considerable sex differences in placental gene expression associated with arsenic exposure, we analyzed male and female samples separately. Results At FDR < 0.05, no genes were differentially expressed in female placenta, while 606 genes were differentially expressed in males. Genes showing the most significant associations with arsenic exposure in females were LEMD1 and UPK3B (fold changes 2.51 and 2.48), and in males, FIBIN and RANBP3L (fold changes 0.14 and 0.15). In gene set enrichment analyses, at FDR < 0.05, a total of 211 gene sets were enriched with differentially expressed genes in female placenta, and 154 in male placenta. In female but not male placenta, 103 of these gene sets were also associated with reduced birth weight. Conclusions Our results reveal multiple biological functions in the fetal placenta that ...
Keywords	Arsenic ; Prenatal ; Placenta ; RNA-seq ; Birth weight ; Proteasome ; Industrial medicine. Industrial hygiene ; RC963-969 ; Public aspects of medicine ; RA1-1270
Subject code	610
Language	English
Publishing date	2019-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The E3 ubiquitin ligase component, Cereblon, is an evolutionarily conserved regulator of Wnt signaling

Nature Communications, Vol 12, Iss 1, Pp 1-

2021 Volume 10

Abstract: Cereblon (CRBN) is an E3 ubiquitin ligase substrate receptor that is involved in cancer cell death, although its regulation is poorly understood. Here, the authors show that Wnt ligand increases CRBN-dependent protein degradation and demonstrate CRBN’s ... ...

Abstract	Cereblon (CRBN) is an E3 ubiquitin ligase substrate receptor that is involved in cancer cell death, although its regulation is poorly understood. Here, the authors show that Wnt ligand increases CRBN-dependent protein degradation and demonstrate CRBN’s importance in physiological Wnt signaling.
Keywords	Science ; Q
Language	English
Publishing date	2021-09-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

Clara Penas / Marie E. Maloof / Vasileios Stathias / Jun Long / Sze Kiat Tan / Jose Mier / Yin Fang / Camilo Valdes / Jezabel Rodriguez-Blanco / Cheng-Ming Chiang / David J. Robbins / Daniel J. Liebl / Jae K. Lee / Mary E. Hatten / Jennifer Clarke / Nagi G. Ayad

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 11

Abstract: The mechanisms controlling irreversible cell cycle exit in cerebellar granule progenitors (GCPs) have not been fully elucidated. Here, the authors performed RNA-sequencing of GCPs exiting the cell cycle to identify downregulation of Brd4 activity as an ... ...

Abstract	The mechanisms controlling irreversible cell cycle exit in cerebellar granule progenitors (GCPs) have not been fully elucidated. Here, the authors performed RNA-sequencing of GCPs exiting the cell cycle to identify downregulation of Brd4 activity as an early event during cell cycle exit which subsequently regulates Shh activity and is needed for proper cerebellar development
Keywords	Science ; Q
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Prenatal arsenic exposure alters the placental expression of multiple epigenetic regulators in a sex-dependent manner

Emily F. Winterbottom / Yuka Moroishi / Yuliya Halchenko / David A. Armstrong / Paul J. Beach / Quang P. Nguyen / Anthony J. Capobianco / Nagi G. Ayad / Carmen J. Marsit / Zhigang Li / Margaret R. Karagas / David J. Robbins

Environmental Health, Vol 18, Iss 1, Pp 1-

2019 Volume 8

Abstract: Abstract Background Prenatal exposure to arsenic has been linked to a range of adverse health conditions in later life. Such fetal origins of disease are frequently the result of environmental effects on the epigenome, leading to long-term alterations in ...

Abstract	Abstract Background Prenatal exposure to arsenic has been linked to a range of adverse health conditions in later life. Such fetal origins of disease are frequently the result of environmental effects on the epigenome, leading to long-term alterations in gene expression. Several studies have demonstrated effects of prenatal arsenic exposure on DNA methylation; however the impact of arsenic on the generation and decoding of post-translational histone modifications (PTHMs) is less well characterized, and has not been studied in the context of prenatal human exposures. Methods In the current study, we examined the effect of exposure to low-to-moderate levels of arsenic in a US birth cohort, on the expression of 138 genes encoding key epigenetic regulators in the fetal portion of the placenta. Our candidate genes included readers, writers and erasers of PTHMs, and chromatin remodelers. Results Arsenic exposure was associated with the expression of 27 of the 138 epigenetic genes analyzed. When the cohort was stratified by fetal sex, arsenic exposure was associated with the expression of 40 genes in male fetal placenta, and only 3 non-overlapping genes in female fetal placenta. In particular, we identified an inverse relationship between arsenic exposure and expression of the gene encoding the histone methyltransferase, PRDM6 (p < 0.001). Mutation of PRDM6 has been linked to the congenital heart defect, patent ductus arteriosus. Conclusions Our findings suggest that prenatal arsenic exposure may have sex-specific effects on the fetal epigenome, which could plausibly contribute to its subsequent health impacts.
Keywords	Arsenic ; Prenatal ; Epigenetic ; Histones ; PRDM6 ; Sex ; Industrial medicine. Industrial hygiene ; RC963-969 ; Public aspects of medicine ; RA1-1270
Subject code	616
Language	English
Publishing date	2019-02-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Time series modeling of cell cycle exit identifies Brd4 dependent regulation of cerebellar neurogenesis

Nature Communications, Vol 10, Iss 1, Pp 1-

2019 Volume 11

Abstract	The mechanisms controlling irreversible cell cycle exit in cerebellar granule progenitors (GCPs) have not been fully elucidated. Here, the authors performed RNA-sequencing of GCPs exiting the cell cycle to identify downregulation of Brd4 activity as an early event during cell cycle exit which subsequently regulates Shh activity and is needed for proper cerebellar development
Keywords	Science ; Q
Language	English
Publishing date	2019-07-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The aquaglyceroporin AQP9 contributes to the sex-specific effects of in utero arsenic exposure on placental gene expression

Emily F. Winterbottom / Devin C. Koestler / Dennis Liang Fei / Eric Wika / Anthony J. Capobianco / Carmen J. Marsit / Margaret R. Karagas / David J. Robbins

Environmental Health, Vol 16, Iss 1, Pp 1-

2017 Volume 9

Abstract: Abstract Background Sex-specific factors play a major role in human health and disease, including responses to environmental stresses such as toxicant exposure. Increasing evidence suggests that such sex differences also exist during fetal development. ... ...

Abstract	Abstract Background Sex-specific factors play a major role in human health and disease, including responses to environmental stresses such as toxicant exposure. Increasing evidence suggests that such sex differences also exist during fetal development. In a previous report using the resources of the New Hampshire Birth Cohort Study (NHBCS), we found that low-to-moderate in utero exposure to arsenic, a highly toxic and widespread pollutant, was associated with altered expression of several key developmental genes in the fetal portion of the placenta. These associations were sex-dependent, suggesting that in utero arsenic exposure differentially impacts male and female fetuses. In the present study, we investigated the molecular basis for these sex-specific responses to arsenic. Methods Using NanoString technology, we further analyzed the fetal placenta samples from the NHBCS for the expression of genes encoding arsenic transporters and metabolic enzymes. Multivariable linear regression analysis was used to examine their relationship with arsenic exposure and with key developmental genes, after stratification by fetal sex. Results We found that maternal arsenic exposure was strongly associated with expression of the AQP9 gene, encoding an aquaglyceroporin transporter, in female but not male fetal placenta. Moreover, AQP9 expression associated with that of a subset of female-specific arsenic-responsive genes. Conclusions Our results suggest that AQP9 is upregulated in response to arsenic exposure in female, but not male, fetal placenta. Based on these results and prior studies, increased AQP9 expression may lead to increased arsenic transport in the female fetal placenta, which in turn may alter the expression patterns of key developmental genes that we have previously shown to be associated with arsenic exposure. Thus, this study suggests that AQP9 may play a role in the sex-specific effects of in utero arsenic exposure.
Keywords	Arsenic ; AQP9 ; in utero ; Fetal placenta ; Industrial medicine. Industrial hygiene ; RC963-969 ; Public aspects of medicine ; RA1-1270
Subject code	616
Language	English
Publishing date	2017-06-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: GLI3 Links Environmental Arsenic Exposure and Human Fetal Growth

Emily F. Winterbottom / Dennis L. Fei / Devin C. Koestler / Camilla Giambelli / Eric Wika / Anthony J. Capobianco / Ethan Lee / Carmen J. Marsit / Margaret R. Karagas / David J. Robbins

EBioMedicine, Vol 2, Iss 6, Pp 536-

2015 Volume 543

Abstract: Although considerable evidence suggests that in utero arsenic exposure affects children's health, these data are mainly from areas of the world where groundwater arsenic levels far exceed the World Health Organization limit of 10 μg/L. We, and others, ... ...

Abstract	Although considerable evidence suggests that in utero arsenic exposure affects children's health, these data are mainly from areas of the world where groundwater arsenic levels far exceed the World Health Organization limit of 10 μg/L. We, and others, have found that more common levels of in utero arsenic exposure may also impact children's health. However, the underlying molecular mechanisms are poorly understood. To address this issue, we analyzed the expression of key developmental genes in fetal placenta in a birth cohort of women using unregulated water supplies in a US region with elevated groundwater arsenic. We identified several genes whose expression associated with maternal arsenic exposure in a fetal sex-specific manner. In particular, expression of the HEDGEHOG pathway component, GLI3, in female placentae was both negatively associated with arsenic exposure and positively associated with infant birth weight. This suggests that modulation of GLI3 in the fetal placenta, and perhaps in other fetal tissues, contributes to arsenic's detrimental effects on fetal growth. We showed previously that arsenic-exposed NIH3T3 cells have reduced GLI3 repressor protein. Together, these studies identify GLI3 as a key signaling node that is affected by arsenic, mediating a subset of its effects on developmental signaling and fetal health.
Keywords	Arsenic ; Development ; GLI3 ; Placenta ; Sex ; Birth Weight ; Medicine ; R
Subject code	616
Language	English
Publishing date	2015-06-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of a Family of Fatty-Acid-Speciated Sonic Hedgehog Proteins, Whose Members Display Differential Biological Properties

Jun Long / Robert Tokhunts / William M. Old / Stephane Houel / Jezabel Rodgriguez-Blanco / Samer Singh / Neal Schilling / Anthony J. Capobianco / Natalie G. Ahn / David J. Robbins

Cell Reports, Vol 10, Iss 8, Pp 1280-

2015 Volume 1287

Abstract: Hedgehog (HH) proteins are proteolytically processed into a biologically active form that is covalently modified by cholesterol and palmitate. However, most studies of HH biogenesis have characterized protein from cells in which HH is overexpressed. We ... ...

Abstract	Hedgehog (HH) proteins are proteolytically processed into a biologically active form that is covalently modified by cholesterol and palmitate. However, most studies of HH biogenesis have characterized protein from cells in which HH is overexpressed. We purified Sonic Hedgehog (SHH) from cells expressing physiologically relevant levels and showed that it was more potent than SHH isolated from overexpressing cells. Furthermore, the SHH in our preparations was modified with a diverse spectrum of fatty acids on its amino termini, and this spectrum of fatty acids varied dramatically depending on the growth conditions of the cells. The fatty acid composition of SHH affected its trafficking to lipid rafts as well as its potency. Our results suggest that HH proteins exist as a family of diverse lipid-speciated proteins that might be altered in different physiological and pathological contexts in order to regulate distinct properties of HH proteins.
Keywords	Biology (General) ; QH301-705.5
Language	English
Publishing date	2015-03-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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