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Article ; Online: MYC cofactors: molecular switches controlling diverse biological outcomes.

Hann, Stephen R

Cold Spring Harbor perspectives in medicine

2014 Volume 4, Issue 9, Page(s) a014399

Abstract: The transcription factor MYC has fundamental roles in proliferation, apoptosis, tumorigenesis, and stem cell pluripotency. Over the last 30 years extensive information has been gathered on the numerous cofactors that interact with MYC and the target ... ...

Abstract	The transcription factor MYC has fundamental roles in proliferation, apoptosis, tumorigenesis, and stem cell pluripotency. Over the last 30 years extensive information has been gathered on the numerous cofactors that interact with MYC and the target genes that are regulated by MYC as a means of understanding the molecular mechanisms controlling its diverse roles. Despite significant advances and perhaps because the amount of information learned about MYC is overwhelming, there has been little consensus on the molecular functions of MYC that mediate its critical biological roles. In this perspective, the major MYC cofactors that regulate the various transcriptional activities of MYC, including canonical and noncanonical transactivation and transcriptional repression, will be reviewed and a model of how these transcriptional mechanisms control MYC-mediated proliferation, apoptosis, and tumorigenesis will be presented. The basis of the model is that a variety of cofactors form dynamic MYC transcriptional complexes that can switch the molecular and biological functions of MYC to yield a diverse range of outcomes in a cell-type- and context-dependent fashion.
MeSH term(s)	Animals ; Apoptosis/genetics ; Cell Transformation, Neoplastic/genetics ; Humans ; Proto-Oncogene Proteins c-myc/genetics ; Signal Transduction ; Transcription, Genetic
Chemical Substances	Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2014-06-17
Publishing country	United States
Document type	Journal Article ; Review
ISSN	2157-1422
ISSN (online)	2157-1422
DOI	10.1101/cshperspect.a014399
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Article: Role of post-translational modifications in regulating c-Myc proteolysis, transcriptional activity and biological function.

Hann, Stephen R

Seminars in cancer biology

2006 Volume 16, Issue 4, Page(s) 288–302

Abstract: The Myc proteins play a central role in cellular proliferation, differentiation, apoptosis and tumorigenesis. Although it is clear that multiple molecular mechanisms mediate these functions, it is unclear how individual mechanisms contribute and if ... ...

Abstract	The Myc proteins play a central role in cellular proliferation, differentiation, apoptosis and tumorigenesis. Although it is clear that multiple molecular mechanisms mediate these functions, it is unclear how individual mechanisms contribute and if different mechanisms work in concert or separately in mediating the diverse biological functions of c-Myc. Similarly, the role of post-translational modifications in regulating c-Myc molecular and biological properties has remained uncertain, despite over 20 years of research. In particular, phosphorylation of the N-terminal transcriptional regulatory domain has been shown to have a variety of consequences ranging from dramatic effects on apoptosis, tumorigenesis and c-Myc proteolysis to negligible effects on cellular transformation and transcriptional activity. This review attempts to provide a comprehensive and critical evaluation of the accumulated evidence to address the complex and controversial issues surrounding the role of post-translational modifications in c-Myc function, focusing on phosphorylation and ubiquitination of the N-terminal transcriptional regulatory domain. An overall model emerges that suggests phosphorylation and ubiquitination play critical roles in cell cycle progression, cell growth, apoptosis and tumorigenesis that are mediated by phosphorylation-dependent transcriptional activation of distinct sets of target genes and synchronized proteolysis.
MeSH term(s)	Animals ; Humans ; Peptide Hydrolases/metabolism ; Phosphorylation ; Protein Processing, Post-Translational ; Protein-Serine-Threonine Kinases/metabolism ; Proto-Oncogene Proteins c-myc/metabolism ; SKP Cullin F-Box Protein Ligases ; Signal Transduction/physiology ; Transcription, Genetic ; Ubiquitins/metabolism
Chemical Substances	Proto-Oncogene Proteins c-myc ; Ubiquitins ; SKP Cullin F-Box Protein Ligases (EC 2.3.2.27) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2006-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	1033980-2
ISSN	1096-3650 ; 1044-579X
ISSN (online)	1096-3650
ISSN	1044-579X
DOI	10.1016/j.semcancer.2006.08.004
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Zs.A 2922: Show issues

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Article ; Online: Association of severe lymphopenia and disease progression in unresectable locally advanced non-small cell lung cancer treated with definitive chemoradiation and immunotherapy.

Friedes, Cole / Chakrabarti, Turja / Olson, Sarah / Prichett, Laura / Brahmer, Julie R / Forde, Patrick M / Voong, Ranh K / Marrone, Kristen A / Lam, Vincent K / Hann, Christine L / Broderick, Stephen R / Battafarano, Richard J / Ha, Jinny S / Bush, Errol L / Yang, Stephen C / Hales, Russel K / Feliciano, Josephine L

Lung cancer (Amsterdam, Netherlands)

2021 Volume 154, Page(s) 36–43

Abstract: Background: Definitive chemoradiation with consolidative immunotherapy offers the best chance for cure in patients with unresectable, locally advanced non-small cell lung cancer (NSCLC). However, treatment-related lymphopenia (TRL) may negatively impact ...

Abstract	Background: Definitive chemoradiation with consolidative immunotherapy offers the best chance for cure in patients with unresectable, locally advanced non-small cell lung cancer (NSCLC). However, treatment-related lymphopenia (TRL) may negatively impact outcomes. Methods: Patients definitively treated with chemoradiation and immunotherapy from 2015 to 2019 at a single tertiary academic center were identified. Severe lymphopenia was defined as <0.5 × 10 Results: Seventy-eight patients were included in the final cohort. The median age was 66 years (IQR: 58-73), 55 % were males, and 88 % had a KPS of >70. At baseline, 90 % (n = 70/78) of patients had a normal ALC and one patient had severe lymphopenia. After chemoradiation, the median ALC decreased from 1.52 × 10 Conclusions: This is the first report to associate severe TRL with disease progression in patients with locally advanced NSCLC receiving consolidative immunotherapy. Factors associated with development of lymphopenia and strategies to mitigate lymphopenic effects should be considered.
MeSH term(s)	Aged ; Carcinoma, Non-Small-Cell Lung/therapy ; Disease Progression ; Female ; Humans ; Immunotherapy/adverse effects ; Lung Neoplasms/therapy ; Lymphopenia/etiology ; Male
Language	English
Publishing date	2021-01-27
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	632771-0
ISSN	1872-8332 ; 0169-5002
ISSN (online)	1872-8332
ISSN	0169-5002
DOI	10.1016/j.lungcan.2021.01.022
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Zs.A 2135: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: The Myc-ARF-Egr1 pathway: unleashing the apoptotic power of c-Myc.

Boone, David N / Hann, Stephen R

Cell cycle (Georgetown, Tex.)

2011 Volume 10, Issue 13, Page(s) 2043–2044

MeSH term(s)	Apoptosis/physiology ; Cyclin-Dependent Kinase Inhibitor Proteins/metabolism ; Early Growth Response Protein 1/metabolism ; Gene Expression Regulation ; Humans ; Proto-Oncogene Proteins c-myc/metabolism ; Signal Transduction/physiology
Chemical Substances	Cyclin-Dependent Kinase Inhibitor Proteins ; Early Growth Response Protein 1 ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2011-06-28
Publishing country	United States
Document type	Editorial
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.10.13.15711
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Article ; Online: Factors affecting embryo viability and uterine receptivity: insights from an analysis of the UK registry data.

Roberts, Stephen A / Hann, Mark / Brison, Daniel R

Reproductive biomedicine online

2015 Volume 32, Issue 2, Page(s) 197–206

Abstract: Many studies have identified prognostic factors for IVF treatment outcome; however, little information is available on the mechanism of their action. Embryo-uterus models have the potential to distinguish between factors acting on the embryo directly and ...

Abstract	Many studies have identified prognostic factors for IVF treatment outcome; however, little information is available on the mechanism of their action. Embryo-uterus models have the potential to distinguish between factors acting on the embryo directly and those acting through the uterine environment. Here we apply embryo-uterus models to comprehensive UK registry data from two periods, 2000-2005 and 2007-2011, containing 139,444 and 226,542 embryo transfer cycles, respectively. Given this large dataset, the embryo-uterus model is capable of distinguishing between uterine and embryo effects. Maternal age is the predominant predictor of live birth and acts on both the embryo and uterine components, but with larger effects on the embryo. Prolonged embryo culture is associated with greater embryo viability, reflecting the greater degree of selection, but is also associated with greater uterine receptivity. Cryopreserved embryos are less viable and were associated with poorer uterine receptivity. This work suggests that, in addition to the direct effects of in-vitro culture on the embryonic environment during the first few days of the embryo's life, the delay in transfer after extended culture or cryopreservation can lead to an altered uterine environment for the embryo after transfer.
MeSH term(s)	Adolescent ; Adult ; Cryopreservation ; Embryo Culture Techniques/methods ; Embryo Implantation ; Embryo Transfer ; Endometrium/physiology ; Female ; Fertilization in Vitro/methods ; Humans ; Live Birth ; Maternal Age ; Middle Aged ; Odds Ratio ; Pregnancy ; Pregnancy Outcome ; Pregnancy Rate ; Registries ; Treatment Outcome ; United Kingdom ; Uterus/physiology ; Young Adult
Language	English
Publishing date	2015-11-11
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2113823-0
ISSN	1472-6491 ; 1472-6483
ISSN (online)	1472-6491
ISSN	1472-6483
DOI	10.1016/j.rbmo.2015.11.002
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Article ; Online: The growth of assisted reproductive treatment-conceived children from birth to 5 years: a national cohort study.

Hann, Mark / Roberts, Stephen A / D'Souza, Stephen W / Clayton, Peter / Macklon, Nick / Brison, Daniel R

BMC medicine

2018 Volume 16, Issue 1, Page(s) 224

Abstract: Background: Birth weight and early child growth are important predictors of long-term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted reproductive technologies (ARTs) occur during ... ...

Abstract	Background: Birth weight and early child growth are important predictors of long-term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted reproductive technologies (ARTs) occur during the sensitive periconceptional window of development, it has recently become a matter of urgency to investigate risk in ART-conceived children. Methods: We have conducted the first large-scale, national cohort study of early growth in ART children from birth to school age, linking the register of ART, held by the UK's Human Fertilisation and Embryology Authority, to Scottish maternity and child health databases. Results: In this study of 5200 ART and 20,800 naturally conceived (NC) control children, linear regression analysis revealed the birthweight of babies born from fresh embryo transfer cycles is 93.7 g [95% CI (76.6, 110.6)g] less than NC controls, whereas babies born from frozen embryo transfer (FET) cycles are 57.5 g [95% CI (30.7, 86.5)g] heavier. Fresh ART babies grew faster from birth (by 7.2 g/week) but remained lighter (by 171 g), at 6-8 weeks, than NC babies and 133 g smaller than FET babies; FET and NC babies were similar. Length and occipital-frontal circumference followed the same pattern. By school entry (4-7 years), weight, length and BMI in boys and girls conceived by fresh ART and FET were similar to those in NC children. Conclusions: ART babies born from fresh embryo transfer grow more slowly in utero and in the first few weeks of life, but then show postnatal catch up growth by school age, compared to NC and FET babies. As low birth weight and postnatal catch-up are independent risk factors for cardiometabolic disease over the life-course, we suggest that further studies in this area are now warranted.
MeSH term(s)	Birth Weight ; Child ; Child Development ; Child, Preschool ; Cohort Studies ; Embryo Transfer/adverse effects ; Embryo Transfer/methods ; Female ; Humans ; Infant ; Infant, Low Birth Weight ; Infant, Newborn ; Male ; Parturition ; Pregnancy ; Pregnancy Outcome ; Risk Factors ; United Kingdom
Language	English
Publishing date	2018-11-28
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1741-7015
ISSN (online)	1741-7015
DOI	10.1186/s12916-018-1203-7
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Article ; Online: Small-molecule high-throughput screening utilizing Xenopus egg extract.

Broadus, Matthew R / Yew, P Renee / Hann, Stephen R / Lee, Ethan

Methods in molecular biology (Clifton, N.J.)

2015 Volume 1263, Page(s) 63–73

Abstract: Screens for small-molecule modulators of biological pathways typically utilize cultured cell lines, purified proteins, or, recently, model organisms (e.g., zebrafish, Drosophila, C. elegans). Herein, we describe a method for using Xenopus laevis egg ... ...

Abstract	Screens for small-molecule modulators of biological pathways typically utilize cultured cell lines, purified proteins, or, recently, model organisms (e.g., zebrafish, Drosophila, C. elegans). Herein, we describe a method for using Xenopus laevis egg extract, a biologically active and highly tractable cell-free system that recapitulates a legion of complex chemical reactions found in intact cells. Specifically, we focus on the use of a luciferase-based fusion system to identify small-molecule modulators that affect protein turnover.
MeSH term(s)	Animals ; Cell-Free System ; Drug Evaluation, Preclinical/methods ; Gene Expression ; High-Throughput Screening Assays ; In Vitro Techniques ; Luciferases/genetics ; Luciferases/metabolism ; Ovum/metabolism ; Recombinant Fusion Proteins/genetics ; Recombinant Fusion Proteins/metabolism ; Small Molecule Libraries ; Xenopus
Chemical Substances	Recombinant Fusion Proteins ; Small Molecule Libraries ; Luciferases (EC 1.13.12.-)
Language	English
Publishing date	2015
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-2269-7_5
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Article ; Online: DNA methylation signature associated with Bohring-Opitz syndrome: a new tool for functional classification of variants in ASXL genes.

Awamleh, Zain / Chater-Diehl, Eric / Choufani, Sanaa / Wei, Elizabeth / Kianmahd, Rebecca R / Yu, Anna / Chad, Lauren / Costain, Gregory / Tan, Wen-Hann / Scherer, Stephen W / Arboleda, Valerie A / Russell, Bianca E / Weksberg, Rosanna

European journal of human genetics : EJHG

2022 Volume 30, Issue 6, Page(s) 695–702

Abstract: The additional sex combs-like (ASXL) gene family-encoded by ASXL1, ASXL2, and ASXL3-is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our ... ...

Abstract	The additional sex combs-like (ASXL) gene family-encoded by ASXL1, ASXL2, and ASXL3-is crucial for mammalian development. Pathogenic variants in the ASXL gene family are associated with three phenotypically distinct neurodevelopmental syndromes. Our previous work has shown that syndromic conditions caused by pathogenic variants in epigenetic regulatory genes show consistent patterns of genome-wide DNA methylation (DNAm) alterations, i.e., DNAm signatures in peripheral blood. Given the role of ASXL1 in chromatin modification, we hypothesized that pathogenic ASXL1 variants underlying Bohring-Opitz syndrome (BOS) have a unique DNAm signature. We profiled whole-blood DNAm for 17 ASXL1 variants, and 35 sex- and age-matched typically developing individuals, using Illumina's Infinium EPIC array. We identified 763 differentially methylated CpG sites in individuals with BOS. Differentially methylated sites overlapped 323 unique genes, including HOXA5 and HOXB4, supporting the functional relevance of DNAm signatures. We used a machine-learning classification model based on the BOS DNAm signature to classify variants of uncertain significance in ASXL1, as well as pathogenic ASXL2 and ASXL3 variants. The DNAm profile of one individual with the ASXL2 variant was BOS-like, whereas the DNAm profiles of three individuals with ASXL3 variants were control-like. We also used Horvath's epigenetic clock, which showed acceleration in DNAm age in individuals with pathogenic ASXL1 variants, and the individual with the pathogenic ASXL2 variant, but not in individuals with ASXL3 variants. These studies enhance our understanding of the epigenetic dysregulation underpinning ASXL gene family-associated syndromes.
MeSH term(s)	Animals ; Craniosynostoses/genetics ; DNA Methylation ; Epigenesis, Genetic ; Humans ; Intellectual Disability/genetics ; Mammals/metabolism ; Syndrome ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	ASXL3 protein, human ; Transcription Factors
Language	English
Publishing date	2022-04-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1141470-4
ISSN	1476-5438 ; 1018-4813
ISSN (online)	1476-5438
ISSN	1018-4813
DOI	10.1038/s41431-022-01083-0
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Zs.A 3589: Show issues

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Article: MB0 and MBI Are Independent and Distinct Transactivation Domains in MYC that Are Essential for Transformation.

Zhang, Qin / West-Osterfield, Kimberly / Spears, Erick / Li, Zhaoliang / Panaccione, Alexander / Hann, Stephen R

Genes

2017 Volume 8, Issue 5

Abstract: MYC is a transcription factor that is essential for cellular proliferation and development. Deregulation or overexpression of MYC occurs in a variety of human cancers. Ectopic expression of MYC causes hyperproliferation and transformation of cells in ... ...

Abstract	MYC is a transcription factor that is essential for cellular proliferation and development. Deregulation or overexpression of MYC occurs in a variety of human cancers. Ectopic expression of MYC causes hyperproliferation and transformation of cells in culture and tumorigenesis in several transgenic mouse models. Deregulation of MYC can also induce apoptosis through activation of p53 and/or ARF tumor suppressors as a safeguard to prevent tumorigenesis. MYC binds to thousands of genomic sites and regulates hundreds of target genes in a context-dependent fashion to mediate these diverse biological roles. The N-terminal region of MYC contains several conserved domains or MYC Boxes (MB), which influence the different MYC transcriptional and biological activities to varying degrees. However, the specific domains that mediate the ability of MYC to activate transcription remain ill defined. In this report, we have identified a new conserved transactivation domain (TAD), MB0, which is essential for MYC transactivation and target gene induction. We demonstrate that MB0 and MBI represent two distinct and independent TADs within the N-terminal 62 amino acids of MYC. In addition, both MB0 and MBI are essential for MYC transformation of primary fibroblasts in cooperation with activated RAS, while MB0 is necessary for efficient MYC-induced p53-independent apoptosis.
Language	English
Publishing date	2017-05-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes8050134
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Article ; Online: The growth of assisted reproductive treatment-conceived children from birth to 5 years

Mark Hann / Stephen A. Roberts / Stephen W. D’Souza / Peter Clayton / Nick Macklon / Daniel R. Brison

BMC Medicine, Vol 16, Iss 1, Pp 1-

a national cohort study

2018 Volume 11

Abstract: Abstract Background Birth weight and early child growth are important predictors of long-term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted reproductive technologies (ARTs) occur ... ...

Abstract	Abstract Background Birth weight and early child growth are important predictors of long-term cardiometabolic disease risk, in line with the Developmental Origins of Health and Disease hypothesis. As human assisted reproductive technologies (ARTs) occur during the sensitive periconceptional window of development, it has recently become a matter of urgency to investigate risk in ART-conceived children. Methods We have conducted the first large-scale, national cohort study of early growth in ART children from birth to school age, linking the register of ART, held by the UK’s Human Fertilisation and Embryology Authority, to Scottish maternity and child health databases. Results In this study of 5200 ART and 20,800 naturally conceived (NC) control children, linear regression analysis revealed the birthweight of babies born from fresh embryo transfer cycles is 93.7 g [95% CI (76.6, 110.6)g] less than NC controls, whereas babies born from frozen embryo transfer (FET) cycles are 57.5 g [95% CI (30.7, 86.5)g] heavier. Fresh ART babies grew faster from birth (by 7.2 g/week) but remained lighter (by 171 g), at 6–8 weeks, than NC babies and 133 g smaller than FET babies; FET and NC babies were similar. Length and occipital-frontal circumference followed the same pattern. By school entry (4–7 years), weight, length and BMI in boys and girls conceived by fresh ART and FET were similar to those in NC children. Conclusions ART babies born from fresh embryo transfer grow more slowly in utero and in the first few weeks of life, but then show postnatal catch up growth by school age, compared to NC and FET babies. As low birth weight and postnatal catch-up are independent risk factors for cardiometabolic disease over the life-course, we suggest that further studies in this area are now warranted.
Keywords	Assisted reproductive technology ; Birth weight ; Child growth ; Data linkage ; Medicine ; R
Subject code	700
Language	English
Publishing date	2018-11-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
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