SELENOP (selenoprotein P, plasma, 1)

2011-03-01 Ewa Jablonska , Jolanta Gromadzinska , Edyta Reszka , Wojciech Wasowicz Affiliation

Nofer Institute of Occupational Medicine, St Teresy 8, 91-348 Lodz, Poland

Identity

HGNC

SELENOP

LOCATION

5p12

LOCUSID

6414

ALIAS

SELP,SEPP,SEPP1,SeP

DNA/RNA

Description

The genomic DNA of SEPP1 spans about 12 kb. SEPP1 consists of 6 exons.

Transcription

3 alternative mRNAs exist encoding 2 different isoforms of selenoprotein P. Transcript variants 1 and 2 encode isoform 1 and transcript variant 3 encodes isoform 2.

Proteins

Note

SEPP1 belongs to selenoproteins, all of which contain selenium in the form of selenocysteine (SeC) and are being synthesized in the presence of UGA codon, specific stem loop structure in 3 UTR of mRNA called SECIS (Selenocysteine Insertion Sequence) and other specific factors. Selenoprotein P is a glycoprotein present mainly in plasma, where it accounts for 40 - 65% of total selenium in this blood compartment. Plasma SEPP1 concentration is regarded as a functional biomarker of human selenium status (Saito and Takahashi, 2002; Méplan et al., 2009; Xia et al., 2010).

Description

Selenoprotein P consists of 381 amino acids and contains ten selenocysteines: nine are located in Sec-rich C-terminal domain (suggested as the region responsible for selenium delivery) and one is present in N-terminal domain (region with redox properties responsible for enzymatic activity of the protein). Two protein isoforms were identified in human plasma: 50 kDa and 60 kDa (Méplan et al., 2007; Méplan et al., 2009).

Expression

SEPP1 is expressed mainly in the liver, from where it is exported to plasma and other tissues. Other organs expressing the protein include mainly brain, thyroid gland, prostate and mammary gland. Its expression has been found to be significantly reduced in cancer, including prostate, colon and lung (Gonzalez-Moreno et al., 2010).
SEPP1 expression is downregulated by different cytokines (Al-Taie et al., 2002). Also hepatic factors such as insulin and glucocorticoids may regulate SEPP1 expression (Speckmann et al., 2008).

Localisation

Plasma.

Function

It is supposed that SeP is responsible for the transport of selenium within body and delivering the microelement to the cells. In brain and testis (organs, in which selenium plays an important role), SEPP1 uptake is mediated by apolipoprotein E receptor-2 (apoER2). In kidneys, the uptake is regulated by another receptor, called megalin (Burk and Hill, 2009) (figure 1).
Additionally, SEPP1 is involved in the reduction of oxidative stress due to its redox properties (Saito et al., 2004).

Figure 1. SEPP1 in selenium homeostasis and transport to the testis, brain and kidney. Whole - body selenium excretion is controlled by selenium excretion in the urine. SEPP1 and selenium excretory metabolites compete for metabolically available selenium in the liver, determining urinary selenium excretion. The lipoprotein receptor apoER2 binds SEPP1 and facilitates its uptake into the testis where selenium is incorporated into spermatozoa. ApoER2 also maintains brain selenium. SEPP1 is filtered by the kidney into the glomerular filtrate and binds to megalin in the brush border of proximal convoluted tubules. Those cells endocytose the SEPP1 bound to megalin and presumably use its selenium to synthesize plasma glutathione peroxidase (GPx3) (adapted from Burk and Hill, 2009, with the authors permission).

Homology

SEPP1 is conserved in chimpanzee, dog, cow, mouse, rat and zebrafish.

Mutations

Note

No mutations in SEPP1 gene have been identified yet.
Genetic variations: several SNPs were identified.
Most often studied polymorphisms within SEPP1:
- Ala234Thr (rs 3877899) - associated with a G/A transition at position 24731 of mRNA, with the amino acid change from alanine to threonine in the codon 234. This polymorphism influences the SePP1 isoform pattern. Using Western blot analysis, it was shown that in the individuals possessing Ala/Ala genotype, 60 kDa protein was a dominating isoform, whereas in those with Ala/Thr genotype, the band for 50 kDa isoform was stronger (Thr/Thr genotype was not analyzed in this study). It was also observed, that within Ala/Ala and Ala/Thr individuals, males had less 60 kDa isoform as compared to females (Méplan et al., 2009).
- r25191g/a (rs 7579) - G/A transition at position 25191 within 3-UTR. Similarly as rs 3877899 SNP, this SNP seems to influence the proportion of SEPP1 isoforms. Individuals with GG genotype had lower proportion of 60 kDa isoform as compared to those with GA or AA genotype (Méplan et al., 2009).
- (TC)5/(TC)3 repeats at promoter region. It was shown in in vitro study that TC3 allele reduced the promoter activity of reporter gene constructs in HepG2 cells (Al-Taie et al., 2002).

Implicated in

Entity name

Cancer

Note

Persson-Moschos et al. (2000) conducted a nested case control study, in which 12500 middle aged men were enrolled and the follow up time was between 1974-1988. Within the studied cohort, SEPP1 plasma concentration was significantly lower in the individuals who were diagnosed with cancer during the follow up (and whose plasma samples were available for analysis, n=302) as compared to control subjects (n=604). The authors of this study suggested that plasma SEPP1 level is associated with higher risk of cancer of respiratory and digestive tract.

Entity name

Colon cancer

Note

Decreased expression of SePP1 mRNA was observed in colorectal cancer tissue as compared with normal colon mucosa (Al-Taie et al., 2004).
The study of 196 cases and 239 controls revealed no association between polymorphism at SEPP1 promoter region (TC)5/(TC)3 repeats and colon cancer risk. However, authors of the study observed genomic instability of Poly-(T)-single nucleotide repeat motif present in the SEPP1 promoter sequence in the colon cancer tissues as compared to normal colon mucosa from the same patients. This instability was observed in 10 out of 51 cases possessing two (TC)5 alleles (no instability was observed in 5 cases with (TC)5/(TC)3 genotype; (TC)3/(TC)3 homozygotes were not present in the studied group) (Al-Taie et al., 2002).
Other study, involving 772 cases and 777 controls, revealed that four SNPs within SEPP1 gene were significantly associated with risk of colorectal adenoma. The SNPs were: SEPP1 -4166G, rs12055266, rs3797310, rs2972994 (Peters et al., 2008).
In the study by Méplan et al. (2009), in which plasma samples from 20 colon cancer patients and 21 healthy individuals were analyzed, significantly lower proportion of 60 kDa isoform was observed in cases with SEPP1 GG genotype of rs 3877899 as compared to controls with the same genotype. Similar (statistically significant) difference between cases and controls was also indicated within individuals possessing GA genotype of rs7579.

Entity name

Prostate cancer

Note

Expression of SEPP1 mRNA was down regulated in human prostate tumours as well as prostate carcinoma cell lines (Calvo et al., 2002).
Further investigation revealed that down-regulation of SEPP1 in prostate cancer cells leads to an increased production of reactive oxygen species (Gonzalez-Moreno et al., 2010).
In the study conducted on 90 males with prostate cancer and 100 control men, it was observed that proteins concentration measured in serum was lower in cases as compared to controls (Meyer et al., 2009).
The interaction between polymorphic variants of SePP1 and SOD2 genes in prostate cancer risk was found by Cooper et al. (2008). According to the results based on CAPS study (Prostate CAncer in Sweden), males being homozygous for SEPP1 Ala234 allele (rs 3877899) and who possessed at least one SOD2 Ala16 allele (rs 4880), were at significantly higher risk of prostate cancer.
In a study of 248 prostate cancer cases and 492 controls, borderline significant association between prostate cancer risk and SEPP1 polymorphism (rs 7579) was found (Steinbrecher et al., 2010).

Bibliography

Pubmed ID	Last Year	Title	Authors
15203372	2004	Expression profiling and genetic alterations of the selenoproteins GI-GPx and SePP in colorectal carcinogenesis.	Al-Taie OH et al
19345254	2009	Selenoprotein P-expression, functions, and roles in mammals.	Burk RF et al
12235003	2002	Alterations in gene expression profiles during prostate cancer progression: functional correlations to tumorigenicity and down-regulation of selenoprotein-P in mouse and human tumors.	Calvo A et al
19074884	2008	Interaction between single nucleotide polymorphisms in selenoprotein P and mitochondrial superoxide dismutase determines prostate cancer risk.	Cooper ML et al
20181815	2010	Establishing optimal selenium status: results of a randomized, double-blind, placebo-controlled trial.	Hurst R et al
17536041	2007	Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender-specific manner (the SELGEN study).	Méplan C et al
20378690	2010	Genetic variants in selenoprotein genes increase risk of colorectal cancer.	Méplan C et al
19453253	2009	Relative abundance of selenoprotein P isoforms in human plasma depends on genotype, se intake, and cancer status.	Méplan C et al
19690186	2009	Reduced serum selenoprotein P concentrations in German prostate cancer patients.	Meyer HA et al
10798212	2000	Selenoprotein P in plasma in relation to cancer morbidity in middle-aged Swedish men.	Persson-Moschos ME et al
18483336	2008	Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma.	Peters U et al
15117283	2004	Domain structure of bi-functional selenoprotein P.	Saito Y et al
12423375	2002	Characterization of selenoprotein P as a selenium supply protein.	Saito Y et al
18972406	2008	Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors.	Speckmann B et al
20852007	2010	Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men.	Steinbrecher A et al
20573787	2010	Optimization of selenoprotein P and other plasma selenium biomarkers for the assessment of the selenium nutritional requirement: a placebo-controlled, double-blind study of selenomethionine supplementation in selenium-deficient Chinese subjects.	Xia Y et al

Other Information

Locus ID:

NCBI: 6414
MIM: 601484
HGNC: 10751
Ensembl: ENSG00000250722

Variants:

dbSNP: 6414
ClinVar: 6414
TCGA: ENSG00000250722
COSMIC: SELENOP

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000250722	ENST00000506577	P49908
ENSG00000250722	ENST00000507920	R4GMT5
ENSG00000250722	ENST00000510965	A0A182DWH8
ENSG00000250722	ENST00000511224	P49908
ENSG00000250722	ENST00000514218	A0A182DWH7
ENSG00000250722	ENST00000514985	P49908

Expression (GTEx)

100

150

200

250

300

350

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Hemostasis	REACTOME	R-HSA-109582
Platelet activation, signaling and aggregation	REACTOME	R-HSA-76002
Response to elevated platelet cytosolic Ca2+	REACTOME	R-HSA-76005
Platelet degranulation	REACTOME	R-HSA-114608

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
21035759	2010	A liver-derived secretory protein, selenoprotein P, causes insulin resistance.	116
17536041	2007	Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender-specific manner (the SELGEN study).	66
17536041	2007	Genetic polymorphisms in the human selenoprotein P gene determine the response of selenoprotein markers to selenium supplementation in a gender-specific manner (the SELGEN study).	66
21677040	2011	Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: implications for insulin resistance, inflammation, and atherosclerosis.	42
18483336	2008	Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma.	41
18483336	2008	Variation in the selenoenzyme genes and risk of advanced distal colorectal adenoma.	41
20852007	2010	Effects of selenium status and polymorphisms in selenoprotein genes on prostate cancer risk in a prospective study of European men.	41
19074884	2008	Interaction between single nucleotide polymorphisms in selenoprotein P and mitochondrial superoxide dismutase determines prostate cancer risk.	40
20378690	2010	Genetic variants in selenoprotein genes increase risk of colorectal cancer.	40
17961124	2008	Hepatic selenoprotein P (SePP) expression restores selenium transport and prevents infertility and motor-incoordination in Sepp-knockout mice.	39

Citation

Ewa Jablonska ; Jolanta Gromadzinska ; Edyta Reszka ; Wojciech Wasowicz

SELENOP (selenoprotein P, plasma, 1)

Atlas Genet Cytogenet Oncol Haematol. 2011-03-01

Online version: http://atlasgeneticsoncology.org/gene/46513/selenop