PUBLICATION

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Authors

Cox, A.G., Tsomides, A., Kim, A.J., Saunders, D., Hwang, K.L., Evason, K.J., Heidel, J., Brown, K.K., Yuan, M., Lien, E.C., Lee, B.C., Nissim, S., Dickinson, B., Chhangawala, S., Chang, C.J., Asara, J.M., Houvras, Y., Gladyshev, V.N., Goessling, W.

ID

ZDB-PUB-160903-3

Date

2016

Source

Proceedings of the National Academy of Sciences of the United States of America 113(38): E5562-71 (Journal)

Registered Authors

Evason, Kimberley, Gladyshev, Vadim, Goessling, Wolfram, Houvras, Yariv, Nissim, Sahar

Keywords

endoderm development, liver cancer, p53, selenium, selenoproteins

Datasets

GEO:GSE85943

MeSH Terms

Oxidation-Reduction
Selenium/metabolism
Humans
Homeostasis
DNA Damage/genetics
DNA-Binding Proteins/genetics*
DNA-Binding Proteins/metabolism
Zebrafish/genetics
Gastrointestinal Neoplasms/genetics*
Gastrointestinal Neoplasms/pathology
Animals
Female
Oxidative Stress/genetics
Selenoproteins/genetics*
Selenoproteins/metabolism
Transcriptome/genetics
Male
Carcinogenesis/genetics*
Gene Expression Regulation, Neoplastic
Tumor Suppressor Protein p53/genetics*

(all 20)

PubMed

27588899 Full text @ Proc. Natl. Acad. Sci. USA

Abstract

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
ccng1	AB	standard conditions	Day 5	whole organism	RTPCR	Fig. 4
ccng1	selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Day 5	whole organism	RTPCR	Fig. 4
elavl3	AB	standard conditions	Day 5	neuron	ISH	Fig. S5
elavl3	AB	standard conditions	Day 5	whole organism	RTPCR	Fig. S5
elavl3	selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Day 5	neuron	ISH	Fig. S5
elavl3	selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Day 5	whole organism	RTPCR	Fig. S5
elavl3	tp53^zdf1/zdf1; selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Day 5	neuron	ISH	Fig. S5
elavl3	tp53^zdf1/zdf1; selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Day 5	whole organism	RTPCR	Fig. S5
fabp10a	AB	control	Protruding-mouth	liver	ISH	Fig. S1
fabp10a	AB	control	Day 5	liver	ISH	Fig. S4

1 - 10 of 44

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB + MO1-selenoh	standard conditions	Protruding-mouth	digestive tract development disrupted, abnormal	Fig. S1
AB + MO1-selenoh	standard conditions	Protruding-mouth	intestine fabp2 expression decreased amount, abnormal	Fig. S1
AB + MO1-selenoh	standard conditions	Protruding-mouth	liver fabp10a expression decreased amount, abnormal	Fig. S1
AB + MO1-selenoh	standard conditions	Protruding-mouth	liver development disrupted, abnormal	Fig. S1
AB + MO1-selenoh	standard conditions	Protruding-mouth	pancreas prss1 expression decreased amount, abnormal	Fig. S1
AB + MO1-selenoh	standard conditions	Protruding-mouth	pancreas development disrupted, abnormal	Fig. S1
selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Protruding-mouth	digestive tract development disrupted, abnormal	Fig. S1
selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Protruding-mouth	head selenoh expression absent, abnormal	Fig. S1
selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Protruding-mouth	intestine fabp2 expression decreased amount, abnormal	Fig. S1
selenoh^{hi2737Tg/hi2737Tg}	standard conditions	Protruding-mouth	liver fabp10a expression decreased amount, abnormal	Fig. S1

1 - 10 of 75

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ae5Tg	Tg(gata6:GFP)	Transgenic Insertion
gz15Tg	Tg(ela3l:EGFP) Tg(fabp10a:DsRed)	Transgenic Insertion
hi2737Tg	Tg(nLacz-GTvirus)	Transgenic Insertion	selenoh
zdf1		Point Mutation	tp53
zf129Tg	Tg(fabp2:DsRed)	Transgenic Insertion

1 - 5 of 5

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Human Disease / Model

Human Disease	Fish	Conditions	Evidence
gastrointestinal system cancer	tp53^zdf1/zdf1; selenoh^hi2737Tg/+	chemical treatment: 7,12-dimethyltetraphene	IC

Sequence Targeting Reagents

Target	Reagent	Reagent Type
selenoh	MO1-selenoh	MRPHLNO

Fish

Fish
AB
AB + MO1-selenoh
selenoh^{hi2737Tg/hi2737Tg}
selenoh^{hi2737Tg/hi2737Tg}; ae5Tg
selenoh^{hi2737Tg/hi2737Tg}; gz15Tg
selenoh^{hi2737Tg/hi2737Tg}; zf129Tg
tp53^zdf1/zdf1; selenoh^{hi2737Tg/hi2737Tg}
tp53^zdf1/zdf1; selenoh^hi2737Tg/+

1 - 8 of 8

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab6-pcna	polyclonal		IgG	Rabbit
Ab10-casp3	polyclonal		IgG	Rabbit
Ab11-tp53	monoclonal	tp53	IgG	Mouse

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Cox et al., 2016 ZDB-PUB-160903-3 PMID:27588899

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Cox et al., 2016

ZDB-PUB-160903-3
PMID:27588899