SEL1L (sel-1 suppressor of lin-12-like (C. elegans))

2005-10-01 Ida Biunno , Monica Cattaneo Affiliation

Istituto Tecnologie Biomediche,V. Fratelli Cervi, 93, 20090 Segrate (MI), Italy

Identity

HGNC

SEL1L

LOCATION

14q31.1

LOCUSID

6400

ALIAS

Hrd3,PRO1063,SEL1-LIKE,SEL1L1

FUSION GENES

Show Gene Fusions

DNA/RNA

A graphical representation of SEL1L isorforms. The black numbered rectangles correspond to the exons, while the white rectangles correspond to the intronic sequence which is retained in the alternative isoforms. The SEL1L domains are indicated on the top of the isoforms. (FN2=fibronectin type II domain;I, II and III clusters of SEL-1 like repeats; Hrd3; TM=transmembrane; P= proline rich domain)

Description

SEL1L genomic size is of 62,24 Kb localized from 81069886 to 81007646. 3 the first exon lies the basal core of the promter, a TATA-less promoter containing four SP1 binding sites and a CAAT box. A CpG island is located between -550bp and the start codon. SEL1L promoter is highly active in pancreatic beta and embryonic kidney cells. The C-terminal tail consists of over 5,0Kb untranslated sequences likely containing key regulatory elements.

Transcription

The sequence is composed of 21 exons and produces at least five different alternative transcripts(A-E) which originate from alternative splicing and putative promoter usage. Exons 1-6 are common to forms A-B-C-E.

Pseudogene

No known pseudogens

Proteins

Note

SEL1L is a multimodular protein consisting of several domains and signal sequences that confer the multifaceted specificities to the molecule

SEL1L protein structure: SEL1L is a multimodular protein containing several structural and functional domains as well as signal sequences. The signal peptide (from 1 to 22 amino acid residues) and the Pest sequence (from 80 to 102 amino acid residues) are represented by red and pink rectangles. The fibronectin type II domain (from 120 to 168 residues) is symbolized by the hexagon (FNII), the SEL-1-like repeats are represented by rhombi and are distributed in tandem along the central portion of the protein in three large clusters (I cluster: 183-326; II cluster: 373-554 and III cluster: 664-675 residues). The Hrd3 like motif is located within the last SEL-1-like repeat (664-675 residues) and is represented by an circle. The transmembrane region (TM) (739-761 residues) and the proline-rich tail (770-793 residues) are symbolized by a blue rectangle. The N-linked glycosilation is also underlined.

Description

SEL1L is not a member of a vast family of proteins but the several described isoforms (over 4) give the appearance of belonging to a multifamily of molecules having perhaps redundant functions.

Expression

Ubiquitously expressed only in fetal and neoplastic tissues. In normal adult tissues is highly expressed in the acini and in the alpha cells of the pancreas; in general is highly represented in secretory cells such as plasma cells.

Localisation

SEL1L protein can have a nuclear, cytoplasmic and nuclear-cytoplasmic location

Function

May have a role in the ER-associated protein degradation (ERAD) system (similarity with Hrd3).

Negative regulator of the NOTCH pathway in C. Elegans.

May play a role in TGF beta signalling.

In breast and pancreatic tumor decrease tumor growth and aggressiveness, possibly involving cell-matrix interaction

Homology

Comparative sequence analysis across different regna, including metazoa, fungi, viridiplantae and bacteria, revealed the remarkable conservation of its primary sequence, although the gene structural complexity increased in evolution. Among mammals, SEL1L shares strict amino acid identity with chimpanzee (99%), dog (97%), hamster (92%), mouse (93%) and rat (92%). It also shows a good similarity with the model organisms such as xenopus (82%), chicken (83%), zebrafish (73%), Drosophila melanogaster (51%) and C. elegans (46%) (Table 1). Arabidopsis thaliana and Saccharomyces cerevisiae display lower similarity (34% and 28%, respectively).

Mutations

Note

Neither causative nor functional mutations were found except for the presence of two base substitutions in the minimal promoter region in two well differentiated lung adenocarcinoma that led to a significant increase in the transcription. A polymorphic base substitution was reported in the fibronectin type II domain of the gene in children affected by persistent hyperinsulinemic hypoglycemia (insulinoma) of infancy which induces a major change in the amino acid composition.

Implicated in

Entity name

Considering the overall results published on SEL1L by various investigators working in different organisms, it can, perhaps, safely be deduced that this gene plays a fundamental role in eukaryotic intracellular protein degradation processes. Protein degradation is becoming a central theme in cancer biology and recently therapeutic approaches that use inhibitors of proteins belonging to ubiquitin-proteosoma pathway have been developed in solid tumors and haematological diseases. A survey of the expression of SEL1L mRNA as well as its encoded protein on a series of cancerous and pre-neoplastic lesion, revealed the role of SEL1L in cancer progression. Furthermore, its expression in breast cancer correlated with patients survival. In vitro studies indicated that SEL1L protein affects those pathways which regulate signalling (cell-cell and or cell-matrix) interactions. Available data derived from several organisms indicate that it may function in the protein degradation processes through ubiquitin-proteosome system and perhaps in regulating important pathways such as Notch and TGF-beta. The fundamental question raised by the observation that SEL1L gets up-modulated during the early steps of tumor transformation is of paramount importance for early diagnosis. Currently it is only possible to hypothesize that the increased SEL1L levels are required in order to meet the advent of genetic and/or genomic structural alterations acquired during cancer initiation or to influence intra-cellular signalling. Its presence may be important in protecting cellular homeostasis from genetic mutations.

Bibliography

Pubmed ID	Last Year	Title	Authors
15095854	2004	Promoter selection for the cytosine deaminase suicide gene constructs in gastric cancer.	Aberle S et al
11349831	2001	SEL1L microsatellite polymorphism in Japanese patients with autoimmune thyroid diseases.	Ban Y et al
15880780	2005	Protein profile changes in the human breast cancer cell line MCF-7 in response to SEL1L gene induction.	Bianchi L et al
9417916	1997	Isolation of a pancreas-specific gene located on human chromosome 14q31: expression analysis in human pancreatic ductal carcinomas.	Biunno I et al
10746565	2000	SEL1L, the human homolog of C. elegans sel-1: refined physical mapping, gene structure and identification of polymorphic markers.	Biunno I et al
12143964	2002	Cross-species conservation of SEL1L, a human pancreas-specific expressing gene.	Biunno I et al
14729273	2004	Identification of a region within SEL1L protein required for tumour growth inhibition.	Cattaneo M et al
12030374	2002	Allele frequency of two intragenic microsatellite loci of SEL1L gene in Northern Italian population.	Chiaramonte R et al
15307954	2004	RNA-mediated interference indicates that SEL1L plays a role in pancreatic beta-cell growth.	Diaferia G et al
10051412	1999	SEL-1L maps to human chromosome 14, near the insulin-dependent diabetes mellitus locus 11.	Donoviel DB et al
15355917	2004	SEL1L and squamous cell carcinoma of the esophagus.	Granelli P et al
10496078	1999	Complete cDNA sequence and genomic organization of a human pancreas-specific gene homologous to Caenorhabditis elegans sel-1.	Harada Y et al
14607247	2003	ER signaling in unfolded protein response.	Kaneko M et al
12882939	2003	Genetic modifiers of the age at diagnosis of diabetes (MODY3) in carriers of hepatocyte nuclear factor-1alpha mutations map to chromosomes 5p15, 9q22, and 14q24.	Kim SH et al
11855798	2001	Complete mutation scanning of the human SEL 1L gene: a candidate gene for type 1 diabetes.	Larsen ZM et al
14666711	2003	Assessing optimal promoter activity for constructs in gastrointestinal gene therapy.	Mathlouthi R et al
11809711	2002	SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro.	Orlandi R et al
15450414	2004	Identification of a novel polymorphism in the fibronectin type II domain of the SEL1L gene and possible relation to the persistent hyperinsulinemic hypoglycemia of infancy.	Saltini G et al

Other Information

Locus ID:

NCBI: 6400
MIM: 602329
HGNC: 10717
Ensembl: ENSG00000071537

Variants:

dbSNP: 6400
ClinVar: 6400
TCGA: ENSG00000071537
COSMIC: SEL1L

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000071537	ENST00000336735	Q9UBV2
ENSG00000071537	ENST00000555824	Q9UBV2
ENSG00000071537	ENST00000557372	G3V3B3

Expression (GTEx)

100

150

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
Protein processing in endoplasmic reticulum	KEGG	ko04141
Protein processing in endoplasmic reticulum	KEGG	hsa04141
HRD1/SEL1 ERAD complex	KEGG	hsa_M00403
HRD1/SEL1 ERAD complex	KEGG	M00403
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Asparagine N-linked glycosylation	REACTOME	R-HSA-446203
N-glycan trimming in the ER and Calnexin/Calreticulin cycle	REACTOME	R-HSA-532668
Calnexin/calreticulin cycle	REACTOME	R-HSA-901042
ER Quality Control Compartment (ERQC)	REACTOME	R-HSA-901032
Disease	REACTOME	R-HSA-1643685
Diseases of signal transduction	REACTOME	R-HSA-5663202
Hh mutants abrogate ligand secretion	REACTOME	R-HSA-5387390
Hh mutants that don't undergo autocatalytic processing are degraded by ERAD	REACTOME	R-HSA-5362768
Disorders of transmembrane transporters	REACTOME	R-HSA-5619115
ABC transporter disorders	REACTOME	R-HSA-5619084
Defective CFTR causes cystic fibrosis	REACTOME	R-HSA-5678895
Signal Transduction	REACTOME	R-HSA-162582
Signaling by NOTCH	REACTOME	R-HSA-157118
Pre-NOTCH Expression and Processing	REACTOME	R-HSA-1912422
Pre-NOTCH Processing in Golgi	REACTOME	R-HSA-1912420
Signaling by Hedgehog	REACTOME	R-HSA-5358351
Hedgehog ligand biogenesis	REACTOME	R-HSA-5358346
Transmembrane transport of small molecules	REACTOME	R-HSA-382551
ABC-family proteins mediated transport	REACTOME	R-HSA-382556

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
18264092	2008	OS-9 and GRP94 deliver mutant alpha1-antitrypsin to the Hrd1-SEL1L ubiquitin ligase complex for ERAD.	229
18711132	2008	SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins.	121
18502753	2008	Human XTP3-B forms an endoplasmic reticulum quality control scaffold with the HRD1-SEL1L ubiquitin ligase complex and BiP.	76
21454652	2011	SEL1L protein critically determines the stability of the HRD1-SEL1L endoplasmic reticulum-associated degradation (ERAD) complex to optimize the degradation kinetics of ERAD substrates.	37
17967421	2007	A different pathway in the endoplasmic reticulum stress-induced expression of human HRD1 and SEL1 genes.	29
24043630	2013	The unfolded protein response transducer ATF6 represents a novel transmembrane-type endoplasmic reticulum-associated degradation substrate requiring both mannose trimming and SEL1L protein.	27
20416077	2010	Identification of type 2 diabetes-associated combination of SNPs using support vector machine.	26
18314878	2008	SEL1L and HRD1 are involved in the degradation of unassembled secretory Ig-mu chains.	23
23363602	2013	The ERdj5-Sel1L complex facilitates cholera toxin retrotranslocation.	23
16331677	2006	SEL1L a multifaceted protein playing a role in tumor progression.	20

Citation

Ida Biunno ; Monica Cattaneo

SEL1L (sel-1 suppressor of lin-12-like (C. elegans))

Atlas Genet Cytogenet Oncol Haematol. 2005-10-01

Online version: http://atlasgeneticsoncology.org/gene/42246/sel1l