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

Identity

Other names	IBD2;
	SEL1-like
HGNC	SEL1L
Location	14q24.3-q31
Local_order	SEL1L is located within a "Gene Desert area" or "Genome Deserts"; centromeric to FLRT2 (fibronectin leucine rich transmembrane protein 2) and telomeric to GTF2A1 (general transcription factor IIA) and (thyroid stimulating hormone receptor) IMAGE

Note	SEL1L is the human ortholog of the C.Elegans sel-1 (suppressor enhancer of lin-12) gene. It shows a high degree of cross-species conservation in its nucleotide and protein sequence.

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. 3ı 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

Protein

	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.

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

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 patientıs 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.

External links

	Nomenclature
HGNC	SEL1L   10717
Entrez_Gene	SEL1L  6400  sel-1 suppressor of lin-12-like (C. elegans)
	Cards
Atlas	SEL1LID42246ch14q24
GeneCards	SEL1L
Ensembl	SEL1L [Search_View]   ENSG00000071537 [Gene_View]
Genatlas	SEL1L
GeneLynx	SEL1L
eGenome	SEL1L
euGene	6400
	Genomic and cartography
GoldenPath	SEL1L  -     chr14:81007646-81069886 -  14q24.3-q31   [Description]    (hg18-Mar_2006)
Ensembl	SEL1L - 14q24.3-q31 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	SEL1L
	Gene and transcription
Genbank	AB020335 [ ENTREZ ]
Genbank	AF052059 [ ENTREZ ]
Genbank	AK075511 [ ENTREZ ]
Genbank	AY358651 [ ENTREZ ]
Genbank	BC040498 [ ENTREZ ]
RefSeq	NM_005065 [ SRS ]    NM_005065 [ ENTREZ ]
RefSeq	AC_000057 [ SRS ]    AC_000057 [ ENTREZ ]
RefSeq	AC_000146 [ SRS ]    AC_000146 [ ENTREZ ]
RefSeq	NC_000014 [ SRS ]    NC_000014 [ ENTREZ ]
RefSeq	NT_026437 [ SRS ]    NT_026437 [ ENTREZ ]
RefSeq	NW_001838113 [ SRS ]    NW_001838113 [ ENTREZ ]
RefSeq	NW_925561 [ SRS ]    NW_925561 [ ENTREZ ]
AceView	SEL1L AceView - NCBI
Unigene	Hs.181300 [ SRS ]    Hs.181300 [ NCBI ]     HS181300 [ spliceNest ]
Fast-db	4255 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	Q12916 [ SRS]    Q12916 [ EXPASY ]     Q12916 [ INTERPRO ]     Q12916 [ UNIPROT ]
Interpro	IPR006597 Sel1_like [ SRS ]    IPR006597 Sel1_like [ EBI ]
Interpro	IPR011990 TPR-like_helical [ SRS ]    IPR011990 TPR-like_helical [ EBI ]
CluSTr	Q12916
Pfam	PF08238 Sel1 [ SRS ]    PF08238 Sel1 [ Sanger ]    pfam08238 [ NCBI-CDD ]
Smart	SM00671 SEL1 [EMBL]
Blocks	Q12916
HPRD	07532
	Protein Interaction databases
DIP	Q12916
IntAct	Q12916
	Polymorphism : SNP, mutations, diseases
OMIM	602329    [ map ]
GENECLINICS	602329
SNP	SEL1L [dbSNP-NCBI]
SNP	NM_005065 [SNP-NCI]
SNP	SEL1L [GeneSNPs - Utah]  SEL1L] [HGBASE - SRS]
HAPMAP	SEL1L [HAPMAP]
COSMIC	SEL1L [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	SEL1L
	General knowledge
Family Browser	SEL1L [UCSC Family Browser]
SOURCE	NM_005065
SMD	Hs.181300
SAGE	Hs.181300
GO	binding [Amigo]  binding
GO	endoplasmic reticulum [Amigo]  endoplasmic reticulum
GO	endoplasmic reticulum membrane [Amigo]  endoplasmic reticulum membrane
GO	Notch signaling pathway [Amigo]  Notch signaling pathway
GO	membrane [Amigo]  membrane
GO	integral to membrane [Amigo]  integral to membrane
PubGene	SEL1L
TreeFam	SEL1L
CTD	6400 [Comparative ToxicoGenomics Database]
	Other databases
Other database	table S7d
	Probes
Probe	SEL1L Related clones (RZPD - Berlin)
	PubMed
PubMed	22 Pubmed reference(s) in LocusLink

Bibliography

Isolation of a pancreas-specific gene located on human chromosome 14q31: expression analysis in human pancreatic ductal carcinomas.

Biunno I, Appierto V, Cattaneo M, Leone BE, Balzano G, Socci C, Saccone S, Letizia A, Della Valle G, Sgaramella V

Genomics. 1997 ; 46 (2) : 284-286.

PMID 9417916

Cloning and characterization of Sel-1l, a murine homolog of the C. elegans sel-1 gene.

Donoviel DB, Donoviel MS, Fan E, Hadjantonakis A, Bernstein A

Mechanisms of development. 1998 ; 78 (1-2) : 203-207.

PMID 9858735

SEL-1L maps to human chromosome 14, near the insulin-dependent diabetes mellitus locus 11.

Donoviel DB, Bernstein A

Genomics. 1999 ; 56 (2) : 232-233.

PMID 10051412

Complete cDNA sequence and genomic organization of a human pancreas-specific gene homologous to Caenorhabditis elegans sel-1.

Harada Y, Ozaki K, Suzuki M, Fujiwara T, Takahashi E, Nakamura Y, Tanigami A

Journal of human genetics. 1999 ; 44 (5) : 330-336.

PMID 10496078

SEL1L, the human homolog of C. elegans sel-1: refined physical mapping, gene structure and identification of polymorphic markers.

Biunno I, Bernard L, Dear P, Cattaneo M, Volorio S, Zannini L, Bankier A, Zollo M

Human genetics. 2000 ; 106 (2) : 227-235.

PMID 10746565

The expression of SEL1L and TAN-1 in normal and neoplastic cells.

Cattaneo M, Orlandi R, Ronchini C, Granelli P, Malferrari G, Menard S, Biunno I

The International journal of biological markers. 2000 ; 15 (1) : 26-32.

PMID 10763137

Cloning and functional analysis of SEL1L promoter region, a pancreas-specific gene.

Cattaneo M, Sorio C, Malferrari G, Rogozin IB, Bernard L, Scarpa A, Zollo M, Biunno I

DNA and cell biology. 2001 ; 20 (1) : 1-9.

PMID 11242538

SEL1L microsatellite polymorphism in Japanese patients with autoimmune thyroid diseases.

Ban Y, Taniyama M, Tozaki T, Yanagawa T, Tomita M, Ban Y

Thyroid : official journal of the American Thyroid Association. 2001 ; 11 (4) : 335-338.

PMID 11349831

Allelic polymorphisms in the transcriptional regulatory region of human SEL1L.

Cattaneo M, Zollo M, Malferrari G, Orlandi R, D'Angelo A, Menard S, Biunno I

Mutation research. 2001 ; 458 (3-4) : 71-76.

PMID 11691638

Complete mutation scanning of the human SEL 1L gene: a candidate gene for type 1 diabetes.

Larsen ZM, Angelo AD, Cattaneo M, Nerup J, Biunno I, Zollo M, Pociot F

Acta diabetologica. 2001 ; 38 (4) : 191-192.

PMID 11855798

Cross-species conservation of SEL1L, a human pancreas-specific expressing gene.

Biunno I, Castiglioni B, Rogozin IB, DeBellis G, Malferrari G, Cattaneo M

Omics : a journal of integrative biology. 2002 ; 6 (2) : 187-198.

PMID 12143964

Notch signal transduction is not regulated by SEL1L in leukaemia and lymphoma cells in culture.

Chiaramonte R, Calzavara E, Basile A, Comi P, Sherbet GV

Anticancer research. 2002 ; 22 (6C) : 4211-4214.

PMID 12553058

Allele frequency of two intragenic microsatellite loci of SEL1L gene in Northern Italian population.

Chiaramonte R, Sabbadini M, Balordi F, Comi P, Sherbet GV

Molecular and cellular biochemistry. 2002 ; 232 (1-2) : 159-161.

PMID 12030374

Production of a monoclonal antibody directed against the recombinant SEL1L protein.

Orlandi R, Cattaneo M, Troglio F, Campiglio M, Biunno I, Mˆİnard S

The International journal of biological markers. 2002 ; 17 (2) : 104-111.

PMID 12113576

SEL1L expression decreases breast tumor cell aggressiveness in vivo and in vitro.

Orlandi R, Cattaneo M, Troglio F, Casalini P, Ronchini C, Mˆİnard S, Biunno I

Cancer research. 2002 ; 62 (2) : 567-574.

PMID 11809711

SEL1L expression in pancreatic adenocarcinoma parallels SMAD4 expression and delays tumor growth in vitro and in vivo.

Cattaneo M, Orlandini S, Beghelli S, Moore PS, Sorio C, Bonora A, Bassi C, Talamini G, Zamboni G, Orlandi R, Mˆİnard S, Bernardi LR, Biunno I, Scarpa A

Oncogene. 2003 ; 22 (41) : 6359-6368.

PMID 14508516

ER signaling in unfolded protein response.

Kaneko M, Nomura Y

Life sciences. 2003 ; 74 (2-3) : 199-205.

PMID 14607247

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, Ma X, Klupa T, Powers C, Pezzolesi M, Warram JH, Rich SS, Krolewski AS, Doria A

Diabetes. 2003 ; 52 (8) : 2182-2186.

PMID 12882939

Assessing optimal promoter activity for constructs in gastrointestinal gene therapy.

Mathlouthi R, Aberle S, Schug N, Kˆşpper JH, Schrˆder K, Seitz G, Blin N

Anticancer research. 2003 ; 23 (5A) : 4011-4015.

PMID 14666711

Promoter selection for the cytosine deaminase suicide gene constructs in gastric cancer.

Aberle S, Schug N, Mathlouthi R, Seitz G, Kˆşpper JH, Schrˆder K, Blin N

European journal of gastroenterology & hepatology. 2004 ; 16 (1) : 63-67.

PMID 15095854

Identification of a region within SEL1L protein required for tumour growth inhibition.

Cattaneo M, Canton C, Albertini A, Biunno I

Gene. 2004 ; 326 : 149-156.

PMID 14729273

RNA-mediated interference indicates that SEL1L plays a role in pancreatic beta-cell growth.

Diaferia G, Cattaneo M, Saltini G, Proverbio MC, Monferini E, Malferrari G, Albertini A, Biunno I

DNA and cell biology. 2004 ; 23 (8) : 510-518.

PMID 15307954

SEL1L and squamous cell carcinoma of the esophagus.

Granelli P, Cattaneo M, Ferrero S, Bottiglieri L, Bosari S, Fichera G, Biunno I

Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 ; 10 (17) : 5857-5861.

PMID 15355917

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, Proverbio MC, Malferrari G, Biagiotti L, Boettcher P, Dominici R, Monferini E, Lorenzini E, Cattaneo M, Antonello D, Moore PS, Zamproni I, Viscardi M, Chiumello G, Biunno I

Mutation research. 2004 ; 554 (1-2) : 159-163.

PMID 15450414

Protein profile changes in the human breast cancer cell line MCF-7 in response to SEL1L gene induction.

Bianchi L, Canton C, Bini L, Orlandi R, Mˆİnard S, Armini A, Cattaneo M, Pallini V, Bernardi LR, Biunno I

Proteomics. 2005 ; 5 (9) : 2433-2442.

PMID 15880780

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Contributor(s)

Written	10-2005	Ida Biunno, Monica Cattaneo
		Istituto Tecnologie Biomediche,V. Fratelli Cervi, 93, 20090 Segrate (MI), Italy

Citation

This paper should be referenced as such :

Biunno I, Cattaneo M . SEL1L (sel-1 suppressor of lin-12-like (C. elegans)). Atlas Genet Cytogenet Oncol Haematol. October 2005 . URL : http://AtlasGeneticsOncology.org/Genes/SEL1LID42246ch14q24.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:17:25 2008