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CSTA (cystatin A (stefin A))

Written2008-07Zala Jevnikar, Janko Kos
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

(Note : for Links provided by Atlas : click)

Identity

Alias_namesSTF1
STFA
cystatin A (stefin A)
Other aliasCystatin-A
Cystatin-AS
Stefin-A
HGNC (Hugo) CSTA
LocusID (NCBI) 1475
Atlas_Id 40180
Location 3q21.1  [Link to chromosome band 3q21]
Location_base_pair Starts at 122325164 and ends at 122341968 bp from pter ( according to hg19-Feb_2009)  [Mapping CSTA.png]
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
CSTA (3q21.1) / CSTA (3q21.1)CSTA (3q21.1) / EPC2 (2q23.1)EPC2 (2q23.1) / CSTA (3q21.1)
INPP5A (10q26.3) / CSTA (3q21.1)MDGA2 (14q21.3) / CSTA (3q21.1)MRPS35 (12p11.22) / CSTA (3q21.1)

DNA/RNA

Description The gene for human stefin A is located on chromosome 3q21 and it comprises three exons of 111 bp, 102 bp and 226 bp in length, while the lengths of the 1st and 2nd intron are approximately 14 Kbp and 4 Kbp, respectively. The conserved sequence of QVVAG is encoded in the 2nd exon and is not inserted by any introns.
Transcription The transcript length of stefin A mRNA is 294 bps. Binding sites for AP-2 (Activating Protein 2) and Sp1 (Selective Promoter Factor 1) regulatory elements are present in the promoter region and an AP-1 (Activating Protein 1) binding site in the 1st intron.

Protein

 
  Ribbon representation of the minimised average structure of stefin A, illustrating the 5-stranded antiparallel b-sheet (with the strands marked A to E) wrapped around the central a-helix with the C-terminal loop running along the convex face of the sheet (Martin et al., 1995).
Description Stefin A belongs to the cystatin superfamily of cysteine protease inhibitors. The lack of a signal sequence and disulfide bonds makes stefins distinct from other members of the cystatin superfamily. Human stefin A is a single chain protein consisting of 98 amino acid residues, with a molecular mass of 11 kDa. Stefin A is an acidic protein with pI values between 4.5 - 5.0. Like other members of the cystatin superfamily, stefin A is reversible and competitive inhibitor of cysteine proteases, particularly cathepsin L and cathepsin S with Ki values in the picomolar range whereas cathepsin B inhibition is weaker (Ki 10-8M) .
Expression Stefin A is expressed and localized most abundantly in epithelial and lymphoid tissue.
Function Besides protection of cytosolyc and cytoskeleton proteins from degradation by cysteine proteases accidentally released from lysosmes, several other functions have been suggested for stefin A. It may be important in the control of normal keratinocyte proliferation and differentiation. Also, it has been proposed to play a role in apoptosis, since apoptotic bodies consistently stain for inhibitor, which also correlates with p53 activation. Stefin A should also protect epithelial and lymphoid tissues from cysteine proteases produced by pathogens invading the body. Increased levels of stefin A were found in inflammatory skin samples and psoriatic epidermis and in inflamed gingival tissue homogenates from patients with periodontal inflammatory diseases. Recent genetic studies identified also mouse stefin A to be involved in a control of ovarian follicular growth and maturation.
Homology Human stefin A exhibit a high degree of homology to other cysteine protease inhibitors of the cystatin superfamily which includes human stefin B and the homologues in other species such as cystatins alpha and beta in rat, bovine thymus stefin C, porcine thymus stefins D1 and D2, mouse stefins A(1-4) and others.

Implicated in

Note
  
Entity Invasive cancers
Disease Higher levels of stefin A in tumours have been determined in lung cancer, breast cancer, head and neck cancer and prostate cancer as well as in murine lymphosarcomas, hepatomas and Lewis lung carcinomas. These higher levels, up to a certain level, may counter-balance the excessive activity of cysteine cathepsins, associated with matrix remodelling resulting in the progression of the disease. On the other hand, high cytosolic levels of stefin A may be relevant for regulation of apoptosis, when initiated via lysosomal cell death pathway inhibiting cathepsin B, which was proposed as a dominant execution protease in the lysosomal apoptotic pathways, induced in a variety of tumour cells by tumour necrosis factor alpha ( TNF-alpha ). In some studies lower levels of stefins in tumours have been reported. For example, stefin A immunoreactivity was lower in lymphomas, in tumours of squamous epithelial cell origin as well as in prostate and brain tumours. Lower mRNA levels of stefin A have been reported in breast and esophagus tumours as compared to adjacent control tissues.
Although stefins are cytosolic proteins, stefin A has also been detected in body fluids of cancer patients, such as ascitic fluid from patients with ovarian carcinoma and in bronhoalveolar fluid of lung cancer patients. Increased serum levels of stefin A in patients with hepatocellular carcinoma and liver cirrhosis correlated with tumour size and with a number of neoplastic lesions. Stefin A were moderately increased also in patients with colorectal cancer or lung cancer.
Prognosis Higher levels of stefin A in tumour tissues have been shown to correlate with a favourable prognosis of cancer patients. A significant prognostic value of stefin A was determined in patients with lung and head and neck cancer. In the latter, high stefin A tumour levels were found as a strong factor for prediction of prognosis also in multivariant analysis when correlated with established clinical parameters. In prostate tumours higher cathepsin B/stefin A ratio were associated with more aggressive behaviour of prostate cancer. On the other hand, higher levels of stefin A in body fluids have been associated with a poor prognosis of cancer patients. Alterations in secretion may result in higher extracellular and lower intracellular levels of stefin A, therefore, a reverse correlation with patient' survival is to be expected.
Oncogenesis Increased levels of cysteine protease activity, not being balanced by a corresponding increase of cysteine protease inhibitors are associated with progression of malignant disease and poor patient's prognosis. Enhanced expression of stefin A would be expected to diminish the tumour-associated proteolytic activity and indeed, there is evidence of a suppressive role of stefin A in various cancer types. Transfection of stefin A cDNA into human EC9706 esophageal squamous cell carcinoma cells inhibits tumour growth, angiogenesis, invasion, and metastasis, and this is mainly through the inhibiting of cathepsin B activity.
  

Bibliography

Friends and relations of the cystatin superfamily--new members and their evolution.
Brown WM, Dziegielewska KM.
Protein Sci. 1997 Jan;6(1):5-12.
PMID 9007972
 
Mapping of the gene for human cysteine proteinase inhibitor stefin A, STF1, to chromosome 3cen-q21.
Hsieh WT, Fong D, Sloane BF, Golembieski W, Smith DI.
Genomics. 1991 Jan;9(1):207-9.
PMID 2004763
 
Towards novel anti-cancer strategies based on cystatin function.
Keppler D.
Cancer Lett. 2006 Apr 28;235(2):159-76.
PMID 15893421
 
Cysteine proteinase inhibitors stefin A, stefin B, and cystatin C in sera from patients with colorectal cancer: relation to prognosis.
Kos J, Krasovec M, Cimerman N, Nielsen HJ, Christensen IJ, Brunner N.
Clin Cancer Res. 2000 Feb;6(2):505-11.
PMID 10690531
 
Cysteine proteinases and their endogenous inhibitors: target proteins for prognosis, diagnosis and therapy in cancer (review).
Kos J, Lah TT.
Oncol Rep. 1998 Nov-Dec;5(6):1349-61.
PMID 9769367
 
Overexpression of stefin A in human esophageal squamous cell carcinoma cells inhibits tumor cell growth, angiogenesis, invasion, and metastasis.
Li W, Ding F, Zhang L, Liu Z, Wu Y, Luo A, Wu M, Wang M, Zhan Q, Liu Z.
Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8753-62.
PMID 16361563
 
The three-dimensional solution structure of human stefin A.
Martin JR, Craven CJ, Jerala R, Kroon-Zitko L, Zerovnik E, Turk V, Waltho JP.
J Mol Biol. 1995 Feb 17;246(2):331-43.
PMID 7869384
 
Characterization by spectroscopic, kinetic and equilibrium methods of the interaction between recombinant human cystatin A (stefin A) and cysteine proteinases.
Pol E, Olsson SL, Estrada S, Prasthofer TW, Bjork I.
Biochem J. 1995 Oct 1;311 ( Pt 1):275-82.
PMID 7575465
 
Expression of acid cysteine proteinase inhibitor (ACPI) in the normal human prostate, benign prostatic hyperplasia and adenocarcinoma.
Soderstrom KO, Laato M, Wu P, Hopsu-Havu VK, Nurmi M, Rinne A.
Int J Cancer. 1995 Jul 4;62(1):1-4.
PMID 7541394
 
Cysteine cathepsins (proteases)--on the main stage of cancer?
Turk V, Kos J, Turk B.
Cancer Cell. 2004 May;5(5):409-10.
PMID 15144947
 

Citation

This paper should be referenced as such :
Jevnikar, Z ; Kos, J
CSTA (cystatin A (stefin A))
Atlas Genet Cytogenet Oncol Haematol. 2009;13(6):403-405.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CSTAID40180ch3q21.html


External links

Nomenclature
HGNC (Hugo)CSTA   2481
Cards
AtlasCSTAID40180ch3q21
Entrez_Gene (NCBI)CSTA  1475  cystatin A
AliasesAREI; PSS4; STF1; STFA
GeneCards (Weizmann)CSTA
Ensembl hg19 (Hinxton)ENSG00000121552 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000121552 [Gene_View]  chr3:122325164-122341968 [Contig_View]  CSTA [Vega]
ICGC DataPortalENSG00000121552
TCGA cBioPortalCSTA
AceView (NCBI)CSTA
Genatlas (Paris)CSTA
WikiGenes1475
SOURCE (Princeton)CSTA
Genetics Home Reference (NIH)CSTA
Genomic and cartography
GoldenPath hg38 (UCSC)CSTA  -     chr3:122325164-122341968 +  3q21.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CSTA  -     3q21.1   [Description]    (hg19-Feb_2009)
EnsemblCSTA - 3q21.1 [CytoView hg19]  CSTA - 3q21.1 [CytoView hg38]
Mapping of homologs : NCBICSTA [Mapview hg19]  CSTA [Mapview hg38]
OMIM184600   607936   
Gene and transcription
Genbank (Entrez)AK291308 AV716538 AV717631 BC010379 BG213814
RefSeq transcript (Entrez)NM_005213
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CSTA
Cluster EST : UnigeneHs.518198 [ NCBI ]
CGAP (NCI)Hs.518198
Alternative Splicing GalleryENSG00000121552
Gene ExpressionCSTA [ NCBI-GEO ]   CSTA [ EBI - ARRAY_EXPRESS ]   CSTA [ SEEK ]   CSTA [ MEM ]
Gene Expression Viewer (FireBrowse)CSTA [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1475
GTEX Portal (Tissue expression)CSTA
Human Protein AtlasENSG00000121552-CSTA [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP01040   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtP01040  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProP01040
Splice isoforms : SwissVarP01040
PhosPhoSitePlusP01040
Domaine pattern : Prosite (Expaxy)CYSTATIN (PS00287)   
Domains : Interpro (EBI)Cystatin_dom    Prot_inh_cystat_CS    Prot_inh_stefinA   
Domain families : Pfam (Sanger)Cystatin (PF00031)   
Domain families : Pfam (NCBI)pfam00031   
Domain families : Smart (EMBL)CY (SM00043)  
Conserved Domain (NCBI)CSTA
DMDM Disease mutations1475
Blocks (Seattle)CSTA
PDB (SRS)1CYU    1CYV    1DVC    1DVD    1GD3    1GD4    1N9J    1NB3    1NB5    3K9M    3KFQ    3KSE   
PDB (PDBSum)1CYU    1CYV    1DVC    1DVD    1GD3    1GD4    1N9J    1NB3    1NB5    3K9M    3KFQ    3KSE   
PDB (IMB)1CYU    1CYV    1DVC    1DVD    1GD3    1GD4    1N9J    1NB3    1NB5    3K9M    3KFQ    3KSE   
PDB (RSDB)1CYU    1CYV    1DVC    1DVD    1GD3    1GD4    1N9J    1NB3    1NB5    3K9M    3KFQ    3KSE   
Structural Biology KnowledgeBase1CYU    1CYV    1DVC    1DVD    1GD3    1GD4    1N9J    1NB3    1NB5    3K9M    3KFQ    3KSE   
SCOP (Structural Classification of Proteins)1CYU    1CYV    1DVC    1DVD    1GD3    1GD4    1N9J    1NB3    1NB5    3K9M    3KFQ    3KSE   
CATH (Classification of proteins structures)1CYU    1CYV    1DVC    1DVD    1GD3    1GD4    1N9J    1NB3    1NB5    3K9M    3KFQ    3KSE   
SuperfamilyP01040
Human Protein Atlas [tissue]ENSG00000121552-CSTA [tissue]
Peptide AtlasP01040
HPRD01697
IPIIPI00032325   IPI00794081   
Protein Interaction databases
DIP (DOE-UCLA)P01040
IntAct (EBI)P01040
FunCoupENSG00000121552
BioGRIDCSTA
STRING (EMBL)CSTA
ZODIACCSTA
Ontologies - Pathways
QuickGOP01040
Ontology : AmiGOcornified envelope  cornified envelope  protease binding  cysteine-type endopeptidase inhibitor activity  structural molecule activity  extracellular space  cytoplasm  cytosol  negative regulation of peptidase activity  negative regulation of endopeptidase activity  single organismal cell-cell adhesion  peptide cross-linking  keratinocyte differentiation  protein binding, bridging  extracellular matrix  negative regulation of proteolysis  extracellular exosome  cornification  
Ontology : EGO-EBIcornified envelope  cornified envelope  protease binding  cysteine-type endopeptidase inhibitor activity  structural molecule activity  extracellular space  cytoplasm  cytosol  negative regulation of peptidase activity  negative regulation of endopeptidase activity  single organismal cell-cell adhesion  peptide cross-linking  keratinocyte differentiation  protein binding, bridging  extracellular matrix  negative regulation of proteolysis  extracellular exosome  cornification  
REACTOMEP01040 [protein]
REACTOME PathwaysR-HSA-6809371 [pathway]   
NDEx NetworkCSTA
Atlas of Cancer Signalling NetworkCSTA
Wikipedia pathwaysCSTA
Orthology - Evolution
OrthoDB1475
GeneTree (enSembl)ENSG00000121552
Phylogenetic Trees/Animal Genes : TreeFamCSTA
HOVERGENP01040
HOGENOMP01040
Homologs : HomoloGeneCSTA
Homology/Alignments : Family Browser (UCSC)CSTA
Gene fusions - Rearrangements
Fusion : MitelmanINPP5A/CSTA [10q26.3/3q21.1]  [t(3;10)(q21;q26)]  
Fusion: TCGA_MDACCINPP5A 10q26.3 CSTA 3q21.1 KIRC
Tumor Fusion PortalCSTA
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCSTA [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CSTA
dbVarCSTA
ClinVarCSTA
1000_GenomesCSTA 
Exome Variant ServerCSTA
ExAC (Exome Aggregation Consortium)ENSG00000121552
GNOMAD BrowserENSG00000121552
Genetic variants : HAPMAP1475
Genomic Variants (DGV)CSTA [DGVbeta]
DECIPHERCSTA [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCSTA 
Mutations
ICGC Data PortalCSTA 
TCGA Data PortalCSTA 
Broad Tumor PortalCSTA
OASIS PortalCSTA [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCSTA  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCSTA
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch CSTA
DgiDB (Drug Gene Interaction Database)CSTA
DoCM (Curated mutations)CSTA (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CSTA (select a term)
intoGenCSTA
NCG5 (London)CSTA
Cancer3DCSTA(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM184600    607936   
Orphanet20746   
DisGeNETCSTA
MedgenCSTA
Genetic Testing Registry CSTA
NextProtP01040 [Medical]
TSGene1475
GENETestsCSTA
Target ValidationCSTA
Huge Navigator CSTA [HugePedia]
snp3D : Map Gene to Disease1475
BioCentury BCIQCSTA
ClinGenCSTA
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1475
Chemical/Pharm GKB GenePA26983
Clinical trialCSTA
Miscellaneous
canSAR (ICR)CSTA (select the gene name)
Probes
Litterature
PubMed81 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCSTA
EVEXCSTA
GoPubMedCSTA
iHOPCSTA
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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