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Article ; Online: ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma

Kimberly J Morgan / Karen Doggett / Fansuo Geng / Stephen Mieruszynski / Lachlan Whitehead / Kelly A Smith / Benjamin M Hogan / Cas Simons / Gregory J Baillie / Ramyar Molania / Anthony T Papenfuss / Thomas E Hall / Elke A Ober / Didier YR Stainier / Zhiyuan Gong / Joan K Heath

eLife, Vol

2023 Volume 12

Abstract: The nucleoporin (NUP) ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an ... ...

Abstract	The nucleoporin (NUP) ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an inducible mutant kras transgene (krasG12V) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly, and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional programme that induces cell death and cell cycle arrest. Heterozygous expression of both ahctf1 and ranbp2 (encoding a second nucleoporin), or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks krasG12V-driven hepatocyte hyperplasia. Gene expression analysis of patient samples in the liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas shows that high expression of one or more of the transcripts encoding the 10 components of the NUP107–160 subcomplex, which includes AHCTF1, is positively correlated with worse overall survival. These results provide a strong and feasible rationale for the development of novel cancer therapeutics that target ELYS function and suggest potential avenues for effective combinatorial treatments.
Keywords	kras oncogene ; ahctf1 ; Elys ; nucleoporin ; synthetic lethality ; hepatocellular carcinoma ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2023-01-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Development of NanoLuc-targeting protein degraders and a universal reporter system to benchmark tag-targeted degradation platforms

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 13

Abstract: tag-Targeted Protein Degrader (tTPD) systems are powerful tools for preclinical target validation. Here the authors extend the tTPD platform by developing NanoTACs that degrade NanoLuc tagged substrates and benchmark each tTPD system using an ... ...

Abstract	tag-Targeted Protein Degrader (tTPD) systems are powerful tools for preclinical target validation. Here the authors extend the tTPD platform by developing NanoTACs that degrade NanoLuc tagged substrates and benchmark each tTPD system using an interchangeable tag reporter system.
Keywords	Science ; Q
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mis-expression of grainyhead-like transcription factors in zebrafish leads to defects in enveloping layer (EVL) integrity, cellular morphogenesis and axial extension

Lee B. Miles / Charbel Darido / Jan Kaslin / Joan K. Heath / Stephen M. Jane / Sebastian Dworkin

Scientific Reports, Vol 7, Iss 1, Pp 1-

2017 Volume 14

Abstract: Abstract The grainyhead-like (grhl) transcription factors play crucial roles in craniofacial development, epithelial morphogenesis, neural tube closure, and dorso-ventral patterning. By utilising the zebrafish to differentially regulate expression of ... ...

Abstract	Abstract The grainyhead-like (grhl) transcription factors play crucial roles in craniofacial development, epithelial morphogenesis, neural tube closure, and dorso-ventral patterning. By utilising the zebrafish to differentially regulate expression of family members grhl2b and grhl3, we show that both genes regulate epithelial migration, particularly convergence-extension (CE) type movements, during embryogenesis. Genetic deletion of grhl3 via CRISPR/Cas9 results in failure to complete epiboly and pre-gastrulation embryonic rupture, whereas morpholino (MO)-mediated knockdown of grhl3 signalling leads to aberrant neural tube morphogenesis at the midbrain-hindbrain boundary (MHB), a phenotype likely due to a compromised overlying enveloping layer (EVL). Further disruptions of grhl3-dependent pathways (through co-knockdown of grhl3 with target genes spec1 and arhgef19) confirm significant MHB morphogenesis and neural tube closure defects. Concomitant MO-mediated disruption of both grhl2b and grhl3 results in further extensive CE-like defects in body patterning, notochord and somite morphogenesis. Interestingly, over-expression of either grhl2b or grhl3 also leads to numerous phenotypes consistent with disrupted cellular migration during gastrulation, including embryo dorsalisation, axial duplication and impaired neural tube migration leading to cyclopia. Taken together, our study ascribes novel roles to the Grhl family in the context of embryonic development and morphogenesis.
Keywords	Medicine ; R ; Science ; Q
Subject code	571
Language	English
Publishing date	2017-12-01T00:00:00Z
Publisher	Nature Publishing Group
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: BAK/BAX-Mediated Apoptosis Is a Myc-Induced Roadblock to Reprogramming

Esther J.Y. Kim / Minna-Liisa Anko / Christoffer Flensberg / Ian J. Majewski / Fan-Suo Geng / Jaber Firas / David C.S. Huang / Mark F. van Delft / Joan K. Heath

Stem Cell Reports, Vol 10, Iss 2, Pp 331-

2018 Volume 338

Abstract: Summary: Despite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and ... ...

Abstract	Summary: Despite intensive efforts to optimize the process, reprogramming differentiated cells to induced pluripotent stem cells (iPSCs) remains inefficient. The most common combination of transcription factors employed comprises OCT4, KLF4, SOX2, and MYC (OKSM). If MYC is omitted (OKS), reprogramming efficiency is reduced further. Cells must overcome several obstacles to reach the pluripotent state, one of which is apoptosis. To directly determine how extensively apoptosis limits reprogramming, we exploited mouse embryonic fibroblasts (MEFs) lacking the two essential mediators of apoptosis, BAK and BAX. Our results show that reprogramming is enhanced in MEFs deficient in BAK and BAX, but only when MYC is part of the reprogramming cocktail. Thus, the propensity for Myc overexpression to elicit apoptosis creates a significant roadblock to reprogramming under OKSM conditions. Our results suggest that blocking apoptosis during reprogramming may enhance the derivation of iPSCs for research and therapeutic purposes. : In this article, Heath, van Delft, and colleagues show that mitochondrial apoptosis limits OKSM-mediated reprogramming of MEFs. Not only is reprogramming of MEFs lacking the two essential mediators of mitochondrial apoptosis, BAK and BAX, significantly enhanced in the presence of MYC, but reprogramming in these conditions does not compromise genome integrity. Keywords: mouse embryonic fibroblasts: reprogramming, induced pluripotent stem cells, mitochondrial apoptosis, BAK, BAX, MYC, p53
Keywords	Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
Subject code	500
Language	English
Publishing date	2018-02-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mediator subunit 12 is required for neutrophil development in zebrafish.

Maria-Cristina Keightley / Judith E Layton / John W Hayman / Joan K Heath / Graham J Lieschke

PLoS ONE, Vol 6, Iss 8, p e

2011 Volume 23845

Abstract: Hematopoiesis requires the spatiotemporal organization of regulatory factors to successfully orchestrate diverse lineage specificity from stem and progenitor cells. Med12 is a regulatory component of the large Mediator complex that enables contact ... ...

Abstract	Hematopoiesis requires the spatiotemporal organization of regulatory factors to successfully orchestrate diverse lineage specificity from stem and progenitor cells. Med12 is a regulatory component of the large Mediator complex that enables contact between the general RNA polymerase II transcriptional machinery and enhancer bound regulatory factors. We have identified a new zebrafish med12 allele, syr, with a single missense mutation causing a valine to aspartic acid change at position 1046. Syr shows defects in hematopoiesis, which predominantly affect the myeloid lineage. Syr has identified a hematopoietic cell-specific requirement for Med12, suggesting a new role for this transcriptional regulator.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2011-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Genetic basis of hindlimb loss in a naturally occurring vertebrate model

Emily K. Don / Tanya A. de Jong-Curtain / Karen Doggett / Thomas E. Hall / Benjamin Heng / Andrew P. Badrock / Claire Winnick / Garth A. Nicholson / Gilles J. Guillemin / Peter D. Currie / Daniel Hesselson / Joan K. Heath / Nicholas J. Cole

Biology Open, Vol 5, Iss 3, Pp 359-

2016 Volume 366

Abstract: Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional ... ...

Abstract	Here we genetically characterise pelvic finless, a naturally occurring model of hindlimb loss in zebrafish that lacks pelvic fin structures, which are homologous to tetrapod hindlimbs, but displays no other abnormalities. Using a hybrid positional cloning and next generation sequencing approach, we identified mutations in the nuclear localisation signal (NLS) of T-box transcription factor 4 (Tbx4) that impair nuclear localisation of the protein, resulting in altered gene expression patterns during pelvic fin development and the failure of pelvic fin development. Using a TALEN-induced tbx4 knockout allele we confirm that mutations within the Tbx4 NLS (A78V; G79A) are sufficient to disrupt pelvic fin development. By combining histological, genetic, and cellular approaches we show that the hindlimb initiation gene tbx4 has an evolutionarily conserved, essential role in pelvic fin development. In addition, our novel viable model of hindlimb deficiency is likely to facilitate the elucidation of the detailed molecular mechanisms through which Tbx4 functions during pelvic fin and hindlimb development.
Keywords	Pelvic fin ; Development ; TALENs ; Hindlimb ; Tbx4 ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2016-03-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Glycoprotein A33 deficiency

Benjamin B. Williams / Niall C. Tebbutt / Michael Buchert / Tracy L. Putoczki / Karen Doggett / Shisan Bao / Cameron N. Johnstone / Frederick Masson / Frederic Hollande / Antony W. Burgess / Andrew M. Scott / Matthias Ernst / Joan K. Heath

Disease Models & Mechanisms, Vol 8, Iss 8, Pp 805-

a new mouse model of impaired intestinal epithelial barrier function and inflammatory disease

2015 Volume 815

Abstract: The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the ... ...

Abstract	The cells of the intestinal epithelium provide a selectively permeable barrier between the external environment and internal tissues. The integrity of this barrier is maintained by tight junctions, specialised cell-cell contacts that permit the absorption of water and nutrients while excluding microbes, toxins and dietary antigens. Impairment of intestinal barrier function contributes to multiple gastrointestinal disorders, including food hypersensitivity, inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Glycoprotein A33 (GPA33) is an intestinal epithelium-specific cell surface marker and member of the CTX group of transmembrane proteins. Roles in cell-cell adhesion have been demonstrated for multiple CTX family members, suggesting a similar function for GPA33 within the gastrointestinal tract. To test a potential requirement for GPA33 in intestinal barrier function, we generated Gpa33−/− mice and subjected them to experimental regimens designed to produce food hypersensitivity, colitis and CAC. Gpa33−/− mice exhibited impaired intestinal barrier function. This was shown by elevated steady-state immunosurveillance in the colonic mucosa and leakiness to oral TRITC-labelled dextran after short-term exposure to dextran sodium sulphate (DSS) to injure the intestinal epithelium. Gpa33−/− mice also exhibited rapid onset and reduced resolution of DSS-induced colitis, and a striking increase in the number of colitis-associated tumours produced by treatment with the colon-specific mutagen azoxymethane (AOM) followed by two cycles of DSS. In contrast, Gpa33−/− mice treated with AOM alone showed no increase in sporadic tumour formation, indicating that their increased tumour susceptibility is dependent on inflammatory stimuli. Finally, Gpa33−/− mice displayed hypersensitivity to food allergens, a common co-morbidity in humans with IBD. We propose that Gpa33−/− mice provide a valuable model to study the mechanisms linking intestinal permeability and multiple inflammatory pathologies. Moreover, this ...
Keywords	GPA33 ; Intestinal permeability ; Colitis ; Colorectal cancer ; Oral tolerance ; Medicine ; R ; Pathology ; RB1-214
Subject code	610
Language	English
Publishing date	2015-08-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A hypermorphic epithelial β-catenin mutation facilitates intestinal tumorigenesis in mice in response to compounding WNT-pathway mutations

Michael Buchert / Franziska Rohde / Moritz Eissmann / Niall Tebbutt / Ben Williams / Chin Wee Tan / Alexander Owen / Yumiko Hirokawa / Alexandra Gnann / Gertraud Orend / Gayle Orner / Rod H. Dashwood / Joan K. Heath / Matthias Ernst / Klaus-Peter Janssen

Disease Models & Mechanisms, Vol 8, Iss 11, Pp 1361-

2015 Volume 1373

Abstract: Activation of the Wnt/β-catenin pathway occurs in the vast majority of colorectal cancers. However, the outcome of the disease varies markedly from individual to individual, even within the same tumor stage. This heterogeneity is governed to a great ... ...

Abstract	Activation of the Wnt/β-catenin pathway occurs in the vast majority of colorectal cancers. However, the outcome of the disease varies markedly from individual to individual, even within the same tumor stage. This heterogeneity is governed to a great extent by the genetic make-up of individual tumors and the combination of oncogenic mutations. In order to express throughout the intestinal epithelium a degradation-resistant β-catenin (Ctnnb1), which lacks the first 131 amino acids, we inserted an epitope-tagged ΔN(1-131)-β-catenin-encoding cDNA as a knock-in transgene into the endogenous gpA33 gene locus in mice. The resulting gpA33ΔN-Bcat mice showed an increase in the constitutive Wnt/β-catenin pathway activation that shifts the cell fate towards the Paneth cell lineage in pre-malignant intestinal epithelium. Furthermore, 19% of all heterozygous and 37% of all homozygous gpA33ΔN-Bcat mice spontaneously developed aberrant crypt foci and adenomatous polyps, at frequencies and latencies akin to those observed in sporadic colon cancer in humans. Consistent with this, the Wnt target genes, MMP7 and Tenascin-C, which are most highly expressed in benign human adenomas and early tumor stages, were upregulated in pre-malignant tissue of gpA33ΔN-Bcat mice, but those Wnt target genes associated with excessive proliferation (i.e. Cdnn1, myc) were not. We also detected diminished expression of membrane-associated α-catenin and increased intestinal permeability in gpA33ΔN-Bcat mice in challenge conditions, providing a potential explanation for the observed mild chronic intestinal inflammation and increased susceptibility to azoxymethane and mutant Apc-dependent tumorigenesis. Collectively, our data indicate that epithelial expression of ΔN(1-131)-β-catenin in the intestine creates an inflammatory microenvironment and co-operates with other mutations in the Wnt/β-catenin pathway to facilitate and promote tumorigenesis.
Keywords	Colorectal cancer ; Mouse models ; GpA33 ; Inflammation ; Medicine ; R ; Pathology ; RB1-214
Subject code	570
Language	English
Publishing date	2015-11-01T00:00:00Z
Publisher	The Company of Biologists
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The Pu.1 target gene Zbtb11 regulates neutrophil development through its integrase-like HHCC zinc finger

Maria-Cristina Keightley / Duncan P. Carradice / Judith E. Layton / Luke Pase / Julien Y. Bertrand / Johannes G. Wittig / Aleksandar Dakic / Andrew P. Badrock / Nicholas J. Cole / David Traver / Stephen L. Nutt / Julia McCoey / Ashley M. Buckle / Joan K. Heath / Graham J. Lieschke

Nature Communications, Vol 8, Iss 1, Pp 1-

2017 Volume 13

Abstract: Neutrophils are increased in response to injury and infection but how they form from a common granulocyte-macrophage progenitor is unclear. Here, the authors identify a role for the transcriptional repressor ZBTB11 in zebrafish, which is regulated by ... ...

Abstract	Neutrophils are increased in response to injury and infection but how they form from a common granulocyte-macrophage progenitor is unclear. Here, the authors identify a role for the transcriptional repressor ZBTB11 in zebrafish, which is regulated by master myeloid regulators and repressesTP53.
Keywords	Science ; Q
Language	English
Publishing date	2017-04-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article: In vivo mutation of pre-mRNA processing factor 8 (Prpf8) affects transcript splicing, cell survival and myeloid differentiation

Keightley, Maria-Cristina / Meredith O. Crowhurst / Judith E. Layton / Traude Beilharz / Sebastian Markmiller / Sony Varma / Benjamin M. Hogan / Tanya A. de Jong-Curtain / Joan K. Heath / Graham J. Lieschke

Federation of European Biochemical Societies FEBS letters. 2013 July 11, v. 587, no. 14

2013

Abstract: Mutated spliceosome components are recurrently being associated with perturbed tissue development and disease pathogenesis. Cephalophŏnus (cph), is a zebrafish mutant carrying an early premature STOP codon in the spliceosome component Prpf8 (pre-mRNA ... ...

Abstract	Mutated spliceosome components are recurrently being associated with perturbed tissue development and disease pathogenesis. Cephalophŏnus (cph), is a zebrafish mutant carrying an early premature STOP codon in the spliceosome component Prpf8 (pre-mRNA processing factor 8). Cph initially develops normally, but then develops widespread cell death, especially in neurons, and is embryonic lethal. Cph mutants accumulate aberrantly spliced transcripts retaining both U2- and U12-type introns. Within early haematopoiesis, myeloid differentiation is impaired, suggesting Prpf8 is required for haematopoietic development. Cph provides an animal model for zygotic PRPF8 dysfunction diseases and for evaluating therapeutic interventions.
Keywords	Danio rerio ; animal models ; cell death ; cell viability ; hematopoiesis ; introns ; mutants ; mutation ; neurons ; pathogenesis ; spliceosomes ; stop codon
Language	English
Dates of publication	2013-0711
Size	p. 2150-2157.
Publishing place	Elsevier B.V.
Document type	Article
ZDB-ID	212746-5
ISSN	1873-3468 ; 0014-5793
ISSN (online)	1873-3468
ISSN	0014-5793
DOI	10.1016/j.febslet.2013.05.030
Database	NAL-Catalogue (AGRICOLA)

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