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THRSP (thyroid hormone responsive)

Identity

Other namesLPGP1
Lpgp
MGC21659
S14
SPOT14
HGNC (Hugo) THRSP
LocusID (NCBI) 7069
Location 11q14.1
Location_base_pair Starts at 77774907 and ends at 77779403 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order According to NCBI Map Viewer, genes flanking THRSP in centromere to telomere direction on 11q13 are:
PHCA (11q13.5), phytoceramidase, alkaline;
GDPD4 (11q13.5), glycerophosphate phosphodiesterase domain containing 4;
PAK1 (11q13-14), p21/cdc42/Rac1-activated kinase1 (STE20 homolog, yeast);
DFKZp434E1119 (11q14.1), hypothetical protein DFKZp434e1119;
AQP11 (11q14.1), aquaporin 11;
THRSP;
LOC646195 (11q14.1), ribosomal protein S28 pseudogene;
LOC143543 (11q14.1), RNA binding motif protein X-linked pseudogene;
RAB30 (11q12-q14), RAB30, member RAS oncogene family;
PCF11 (11q13), PCF11, cleavage and polyadenylation factor subunit, homolog (S. cerevisiae).

DNA/RNA

 
  An intron (thin line) connects the two exons of THRSP. Most of the 5' exon (thickest line) is translated.
Description According to Entrez-Gene, THRSP maps to NC_000011.9 in the region between 77774907 and 77779307 on the plus strand and spans 5.6 kilobases. According to Spidey (mRNA to genomic sequence alignment tool), THRSP has two exons, the sizes being 481 and 603 bp. Only the smaller of these is translated.
Transcription THRSP mRNA NM_003251.2 has 1084 nt. The coding region of human mRNA for THRSP has 438 nt. Transcription is regulated via thyroid hormone and the SREBP-1c binding sites. Expression can be induced by progestin, glucose, thyroid hormone, and insulin. Antisense RNA knocks down S14 expression in hepatocytes, and this abrogates the induction of genes concerned with fatty acid synthesis by triiodothyronine and glucose.
Pseudogene The ancestral S14-related protein, also known as Strait 11499 and Mig12, may duplicate the function of S14 in hepatic, but not mammary, tissue.

Protein

Note THRSP is primarily a nuclear protein which is important in the regulation of lipid metabolism. It is induced by thyroid hormone, carbohydrate intake, adipose tissue differentiation, and lactation, and is inhibited by glucagon and conjugated linoleic acid. Expression of THRSP (Spot14) parallels that of fatty acid synthase in adipose, liver, and mammary tissue in bovine and murine species. Elevated expression of THRSP in human breast tumors is correlated with poor prognosis, whereas absence of expression is associated with longer survival.
Description A driver of de novo saturated fatty acid synthesis in normal and malignant tissues, Spot14 (S14, THRSP) was named for its position on two-dimensional gels of in vitro translation products. The gene is rapidly induced by thyroid hormone in rat liver, and it is strongly activated by glucose metabolism. An acidic protein of approximately 16 kD, it is localized primarily in the nucleus; three domains are conserved from its ancestral protein, Strait1499, also known as Mig12 and S14-related protein.
From immunohistochemical studies, the temporal and spatial expression patterns of murine Spot14 and fatty acid synthase (FASN) were regulated in parallel in mammary epithelium during pregnancy, lactation, and involution. In cattle, milk fat depression is associated with production of conjugated linoleic acid (CLA) isomers as intermediates of fatty acid synthesis by rumen bacteria. Ingestion of a low forage, high oil diet leads to increased production of CLA, and this results in low milk fat content, and decreased expression of S14, FASN, sterol response element binding protein (SREBP), and responsive genes INSIG1 and INSIG2 in a coordinate manner. Breast epithelium does not express detectable levels of Spot14 or FASN in the resting state; however, during pregnancy and lactation, Spot14 and enzymes of lipid biosynthesis are expressed at high levels. Spot14 and FASN are expressed in most breast cancers, and high levels of Spot14 expression portend an aggressive course and high risk of recurrence, regardless of nodal status at diagnosis. Thus Spot14 represents a potential target for therapeutic intervention in cancer.
Expression Spot14 protein is expressed primarily in tissues which synthesize fatty acids. These tissues include white and brown adipose tissue, breast tissue, and liver. Expression is observed in a variety of malignancies, and it is a component of the lipogenic tumor phenotype, e.g., in human breast cancer.
Localisation By immunohistochemistry, Spot14 is localized primarily in the nucleus of rat liver, human mammary gland, and breast cancer cells.
Function Spot14 is involved in the regulation of lipid biosynthesis. Its precise function is not known. It exists as a heterodimer in human cells which are actively synthesizing lipids. Triggers for the induction of Spot14, such as hormones or refeeding after fasting, also trigger FASN activity. Furthermore, siRNAs and anti-sense RNAs directed against Spot14 inhibit expression of genes coding the lipid-synthesizing enzymes.
Homology Homologous proteins are found in cow, rat, mouse, chicken, dog, and chimpanzee, as well as other species. An acidic protein of approximately 16.4 kDa, human THRSP bears 99% homology to its counterpart in Pan troglodytes, 91% to that in Macaca mulatta, 82% to that in Mus musculus, and 80% to that in Rattus norvegicus (data from NCBI BLAST). Three domains are conserved from the ancestral S14-related peptide (Strait 11499, Mig12, S14-related protein).

Mutations

Note Mutations have been characterized in the chicken. Single-nucleotide polymorphisms (SNPs) have been noted in cow, rat, mouse, and chimpanzee. The SNP database in NCBI lists 63 human SNPs for THRSP.

Implicated in

Entity Breast tumors
Note Along with cyclin D1, which shares the same amplicon at 11q13, S14 is amplified in about 20% of human breast cancers. Although cyclin D1 is a human and murine mammary oncogene, it was the concomitant overexpression of S14 and lipogenic enzymes in aggressive breast tumors that prompted investigation of the role of fatty acid metabolism in metastasis and recurrence of breast tumors. In an immunohistochemical study of invasive breast tumors, high levels of S14 expression correlated with reduced disease-free survival, irrespective of nodal status at diagnosis; there were no recurrences among those whose tumors expressed low levels of S14, even after prolonged follow-up. S14 expression levels did not segregate with cyclin D1, Her-2/neu amplification status, or hormone receptor status. Thus it appears that S14 promotes a virulent, lipogenic phenotype in breast tumors.
  
Entity Aberrant hepatic lipogenesis and hepatic steatosis
Note The relationship between lipid metabolism and disease is further corroborated by the finding in human hepatocytes that the pregnane X receptor (PXR), which is a nuclear receptor regulating xenobiotic and drug metabolism, upregulates lipogenesis via S14. Stimulation of PXR also enhances expression of the cd36 gene, which permits the uptake of exogenous fatty acids by cells, and also stimulates de novo lipogenesis as well as upregulation of the enzymes involved in lipid synthesis. Knockdown by short interfering RNAs to PXR, S14, or FASN abrogates lipid synthesis. S14-directed fatty acid synthesis has also been implicated in aberrant hepatic lipogenesis and hepatic steatosis.
  
Entity Obesity
Note It is possible that Spot14 plays a role in the regulation of lipid storage in humans. Whereas nonobese humans downregulate the level of Spot14 in response to fasting, obese subjects do not. Postfasting levels of glucose, insulin, and ketones did not differ between the two groups. The abnormal downregulation of Spot14 in adipose tissue of obese subjects implies that Spot14 may be important to the acquisition or maintenance of obesity in humans.
  

External links

Nomenclature
HGNC (Hugo)THRSP   11800
Cards
AtlasTHRSPID42555ch11q14
Entrez_Gene (NCBI)THRSP  7069  thyroid hormone responsive
GeneCards (Weizmann)THRSP
Ensembl (Hinxton)ENSG00000151365 [Gene_View]  chr11:77774907-77779403 [Contig_View]  THRSP [Vega]
AceView (NCBI)THRSP
Genatlas (Paris)THRSP
WikiGenes7069
SOURCE (Princeton)NM_003251
Genomic and cartography
GoldenPath (UCSC)THRSP  -  11q14.1   chr11:77774907-77779403 +  11q14.1   [Description]    (hg19-Feb_2009)
EnsemblTHRSP - 11q14.1 [CytoView]
Mapping of homologs : NCBITHRSP [Mapview]
OMIM601926   
Gene and transcription
Genbank (Entrez)AI480357 AI749106 AK311975 BC031989 BG674197
RefSeq transcript (Entrez)NM_003251
RefSeq genomic (Entrez)AC_000143 NC_000011 NC_018922 NT_167190 NW_001838028 NW_004929380
Consensus coding sequences : CCDS (NCBI)THRSP
Cluster EST : UnigeneHs.591969 [ NCBI ]
CGAP (NCI)Hs.591969
Alternative Splicing : Fast-db (Paris)GSHG0005138
Alternative Splicing GalleryENSG00000151365
Gene ExpressionTHRSP [ NCBI-GEO ]     THRSP [ SEEK ]   THRSP [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ92748 (Uniprot)
NextProtQ92748  [Medical]
With graphics : InterProQ92748
Splice isoforms : SwissVarQ92748 (Swissvar)
Domains : Interpro (EBI)Spot_14   
Related proteins : CluSTrQ92748
Domain families : Pfam (Sanger)Spot_14 (PF07084)   
Domain families : Pfam (NCBI)pfam07084   
DMDM Disease mutations7069
Blocks (Seattle)Q92748
Human Protein AtlasENSG00000151365
Peptide AtlasQ92748
HPRD03566
IPIIPI00023246   
Protein Interaction databases
DIP (DOE-UCLA)Q92748
IntAct (EBI)Q92748
FunCoupENSG00000151365
BioGRIDTHRSP
InParanoidQ92748
Interologous Interaction database Q92748
IntegromeDBTHRSP
STRING (EMBL)THRSP
Ontologies - Pathways
Ontology : AmiGOnucleus  nucleolus  cytosol  transcription, DNA-templated  regulation of transcription, DNA-dependent  lipid metabolic process  regulation of triglyceride biosynthetic process  protein homodimerization activity  regulation of lipid biosynthetic process  
Ontology : EGO-EBInucleus  nucleolus  cytosol  transcription, DNA-templated  regulation of transcription, DNA-dependent  lipid metabolic process  regulation of triglyceride biosynthetic process  protein homodimerization activity  regulation of lipid biosynthetic process  
REACTOMETHRSP
Protein Interaction DatabaseTHRSP
Wikipedia pathwaysTHRSP
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)THRSP
SNP (GeneSNP Utah)THRSP
SNP : HGBaseTHRSP
Genetic variants : HAPMAPTHRSP
1000_GenomesTHRSP 
ICGC programENSG00000151365 
Somatic Mutations in Cancer : COSMICTHRSP 
CONAN: Copy Number AnalysisTHRSP 
Mutations and Diseases : HGMDTHRSP
OMIM601926   
GENETestsTHRSP
Disease Genetic AssociationTHRSP
Huge Navigator THRSP [HugePedia]  THRSP [HugeCancerGEM]
Genomic VariantsTHRSP  THRSP [DGVbeta]
Exome VariantTHRSP
dbVarTHRSP
ClinVarTHRSP
snp3D : Map Gene to Disease7069
General knowledge
Homologs : HomoloGeneTHRSP
Homology/Alignments : Family Browser (UCSC)THRSP
Phylogenetic Trees/Animal Genes : TreeFamTHRSP
Chemical/Protein Interactions : CTD7069
Chemical/Pharm GKB GenePA36509
Clinical trialTHRSP
Cancer Resource (Charite)ENSG00000151365
Other databases
Probes
Litterature
PubMed18 Pubmed reference(s) in Entrez
CoreMineTHRSP
iHOPTHRSP

Bibliography

Thyroid hormone attenuates and augments hepatic gene expression at a pretranslational level.
Seelig S, Liaw C, Towle HC, Oppenheimer JH.
Proc Natl Acad Sci U S A. 1981 Aug;78(8):4733-7.
PMID 6946422
 
Thyroid hormone and dietary carbohydrate induce different hepatic zonation of both "spot 14" and acetyl-coenzyme-A carboxylase: a novel mechanism of coregulation.
Kinlaw WB, Tron P, Witters LA.
Endocrinology. 1993 Aug;133(2):645-50.
PMID 8102096
 
Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer.
Dickson C, Fantl V, Gillett C, Brookes S, Bartek J, Smith R, Fisher C, Barnes D, Peters G.
Cancer Lett. 1995 Mar 23;90(1):43-50. (REVIEW)
PMID 7720042
 
Direct evidence for a role of the "spot 14" protein in the regulation of lipid synthesis.
Kinlaw WB, Church JL, Harmon J, Mariash CN.
J Biol Chem. 1995 Jul 14;270(28):16615-8.
PMID 7622469
 
"Spot 14" protein functions at the pretranslational level in the regulation of hepatic metabolism by thyroid hormone and glucose.
Brown SB, Maloney M, Kinlaw WB.
J Biol Chem. 1997 Jan 24;272(4):2163-6.
PMID 8999918
 
Assignment of the "spot 14" gene (THRSP) to human chromosome band 11q13.5 by in situ hybridization.
Moncur JT, Park JP, Maloney M, Mohandas TK, Kinlaw WB.
Cytogenet Cell Genet. 1997;78(2):131-2.
PMID 9371405
 
Adipose S14 mRNA is abnormally regulated in obese subjects.
Kirschner LS, Mariash CN.
Thyroid. 1999 Feb;9(2):143-8.
PMID 10090313
 
Sterol response element-binding protein 1c (SREBP1c) is involved in the polyunsaturated fatty acid suppression of hepatic S14 gene transcription.
Mater MK, Thelen AP, Pan DA, Jump DB.
J Biol Chem. 1999 Nov 12;274(46):32725-32.
PMID 10551830
 
Spot 14 protein interacts and co-operates with chicken ovalbumin upstream promoter-transcription factor 1 in the transcription of the L-type pyruvate kinase gene through a specificity protein 1 (Sp1) binding site.
Compe E, de Sousa G, Francois K, Roche R, Rahmani R, Torresani J, Raymondjean M, Planells R.
Biochem J. 2001 Aug 15;358(Pt 1):175-83.
PMID 11485565
 
Activation of fatty acid synthesis during neoplastic transformation: role of mitogen-activated protein kinase and phosphatidylinositol 3-kinase.
Yang YA, Han WF, Morin PJ, Chrest FJ, Pizer ES.
Exp Cell Res. 2002 Sep 10;279(1):80-90.
PMID 12213216
 
Duplicated Spot 14 genes in the chicken: characterization and identification of polymorphisms associated with abdominal fat traits.
Wang X, Carre W, Zhou H, Lamont SJ, Cogburn LA.
Gene. 2004 May 12;332:79-88.
PMID 15145057
 
SREBP1 and thyroid hormone responsive spot 14 (S14) are involved in the regulation of bovine mammary lipid synthesis during diet-induced milk fat depression and treatment with CLA.
Harvatine KJ, Bauman DE.
J Nutr. 2006 Oct;136(10):2468-74.
PMID 16988111
 
Spot 14: A marker of aggressive breast cancer and a potential therapeutic target.
Kinlaw WB, Quinn JL, Wells WA, Roser-Jones C, Moncur JT.
Endocrinology. 2006 Sep;147(9):4048-55. Epub 2006 Jun 29. (REVIEW)
PMID 16809441
 
S14 protein in breast cancer cells: direct evidence of regulation by SREBP-1c, superinduction with progestin, and effects on cell growth.
Martel PM, Bingham CM, McGraw CJ, Baker CL, Morganelli PM, Meng ML, Armstrong JM, Moncur JT, Kinlaw WB.
Exp Cell Res. 2006 Feb 1;312(3):278-88. Epub 2005 Nov 21.
PMID 16300755
 
Expression of "Spot 14" (THRSP) predicts disease free survival in invasive breast cancer: immunohistochemical analysis of a new molecular marker.
Wells WA, Schwartz GN, Morganelli PM, Cole BF, Gibson JJ, Kinlaw WB.
Breast Cancer Res Treat. 2006 Jul;98(2):231-40. Epub 2006 Mar 22.
PMID 16552628
 
Hepatic expression of the SPOT 14 (S14) paralog S14-related (Mid1 interacting protein) is regulated by dietary carbohydrate.
Tsatsos NG, Augustin LB, Anderson GW, Towle HC, Mariash CN.
Endocrinology. 2008 Oct;149(10):5155-61. Epub 2008 Jun 12.
PMID 18556348
 
A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte.
Moreau A, Teruel C, Beylot M, Albalea V, Tamasi V, Umbdenstock T, Parmentier Y, Sa-Cunha A, Suc B, Fabre JM, Navarro F, Ramos J, Meyer U, Maurel P, Vilarem MJ, Pascussi JM.
Hepatology. 2009 Jun;49(6):2068-79.
PMID 19437491
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written09-2010Nancy B Kuemmerle, William B Kinlaw
Dept of Physiology, Dartmouth Medical School - Lebanon, New Hampshire, USA (NBK); Norris Cotton Cancer Center at Dartmouth Medical School - Lebanon, New Hampshire, USA (NBK, WBK); Dept of Medicine, Section of Endocrinology and Metabolism, Dartmouth Medical School - Lebanon, New Hampshire, USA (WBK)

Citation

This paper should be referenced as such :
Kuemmerle NB, Kinlaw WB . THRSP (thyroid hormone responsive). Atlas Genet Cytogenet Oncol Haematol. September 2010 .
URL : http://AtlasGeneticsOncology.org/Genes/THRSPID42555ch11q14.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/45032/1/09-2010-THRSPID42555ch11q14.pdf   [ Bibliographic record ]

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