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CSTB (cystatin B (stefin B))

Identity

Other namesCPI-B
CST6
Cystatin-B
EPM1
PME
STFB
Stefin-B
HGNC (Hugo) CSTB
LocusID (NCBI) 1476
Location 21q22.3
Location_base_pair Starts at 45193546 and ends at 45196256 bp from pter ( according to hg19-Feb_2009)  [Mapping]

DNA/RNA

Description The stefin B gene is located on human chromosome 21q22.3 and it contains 3 exons and 2 introns. The transcript length of stefin B mRNA is 294 bps. A novel variant, with retention of the entire intron 2 is transcribed from two exons with an ORF of 249 bp. It encodes a putative 9.0-kDa protein of 83 amino acids, including 57 identical to stefin B followed by 26 amino acids encoded by the intron 2 sequences.

Protein

 
  Richardson diagram of stefin B structure: alpha-helixes are shown in red and beta-sheets in green (MEROPS: the peptidase database - I25.003: cystatin B).
Description The cystatin superfamily comprises at least four families of closely related proteins, such as stefins (family I), cystatins (family II), kininogens (family III), and various structurally related but noninhibitory proteins of family IV. A significant structural difference between stefins and cystatins is the signal peptide, which is responsible for extracellular targeting of cystatins, whereas stefins lack this peptide and have been reported as intracellular inhibitors. Human stefin B is a single chain protein consisting of 98 amino acid residues, with a molecular mass of 11,175 kDa. Stefin B is a neutral protein with pI values between 5.9 - 6.5 and is able to form a dimmer stabilized by noncovalent forces. Like other members of the cystatin superfamily, stefin B 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 10-7M).
Expression Stefin B is widely distributed among different cell types and tissues. Although it lacks an export signal sequence and is generally thought to function intracellularly, it has also been found in extracellular fluid.
Function Stefin B is thought to play a role in protecting cytosolic and cytoskeleton proteins against the cysteine proteases accidentally released from lysosomes. Besides protease inactivation stefin B could bind other proteins in a multiprotein complex which might contribute to the disease in patients with progressive myoclonus epilepsy. Decreased levels of stefin B mRNA were detected in patients with progressive myoclonus epilepsy and associated with excessive activity of cathepsin B. Moreover, stefin B may be important in the control of osteoclasts bone resorption. It inhibits bone resorption by down-regulating intracellular cathepsin K activity. On the other hand stefin B protected osteoclasts from experimentally induced apoptosis, promoting cell survival in the nervous system.
Homology Human stefin B exhibit a high degree of homology to other cysteine protease inhibitors of the cystatin superfamily which includes human stefin A and the homologues in other species. It is 79% identical with cystatin beta from rat liver, but contains only a single cysteine.

Mutations

Note Eight mutations in the stefin B gene have been reported to associate with an autosomal recessive neurodegenerative disorder, progressive myoclonus epilepsy of Unverricht-Lundborg type (EPM1). Most of the disease alleles harbour an unstable expansion of at least 30 copies of a normally polymorphic 12-nucleotide, dodecamer repeat located in the promoter region of the stefin B gene. Three reported EPM1 mutations affect splice sites, two result in amino-acid changes and two predict truncated proteins either through creating a stop codon or producing a frameshift.

Implicated in

Entity Invasive cancers
Disease Higher levels of stefin B in tumours have been determined in lung, breast, head and neck 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 stefins 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. Lower mRNA levels of stefin B have been reported in breast and esophagus tumours as compared to adjacent control tissues.
Although stefins are cytosolic proteins, they have also been detected in body fluids of cancer patients. Stefin B has been detected in ascitic fluid from patients with ovarian carcinoma and in bronhoalveolar fluid of lung cancer patients.
Diagnosis: The poor survival rate of hepatocellular carcinoma is in part due to the inability to diagnose patients at an early stage. Stefin B is specifically overexpressed in most hepatocellular carcinoma and is also elevated in the serum of a large proportion of hepatocellular carcinoma patients. Stefin B may be a useful marker for diagnosing patients with hepatocellular carcinoma with a high sensitivity.
Prognosis Higher levels of stefin B in tumour tissues have been shown to correlate with a favourable prognosis of cancer patients. A significant prognostic value of stefin B was determined in patients with lung and head and neck cancer. On the other hand, animal model with excluded expression of stefin B did not support its suppressive function in cancer. A significantly lower metastatic spread was detected in stefin B knock-out mice than in wild-type animals. Similarly, higher levels of stefin B 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 stefins and, 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 B would be expected to diminish the tumour-associated proteolytic activity and indeed, there is evidence of a suppressive role of stefin B in various cancer types.
  
Entity Progressive myoclonus epilepsy
Disease The progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is an autosomal recessive disease characterized by progressive myoclonic jerks and decline in cognition. Genetic linkage studies, suggest the involvement of the stefin B gene. A decreased amount of stefin B mRNA is a common finding in EPM1 patients and it may be due to: 1) a mutation in the promoter region causing a decrease in the rate of transcription of the gene or 2) mutations of the coding region/splice sites that may inhibit translation or diminish the half-life of the transcript and/or of the protein. The availability of a stefin B knock-out mouse as a model for the disease has allowed identification of the presence of severe apoptotic damage to the cerebellar granule cells. This observation combined with the anti-protease function of stefin B protein has suggested that it may have an anti-apoptotic function in the cerebellum. It was shown that a number of proteins (manly proteins that are involved in the regulation of cytoskeletal functions) that are not proteases can interact specifically with stefin B, forming a multiprotein complex. The first hypothesis is that stefin B may be active as antiprotease, protecting the complex against the attack of proteases. An alternative hypothesis is that stefin B may bind to the interacting proteins modifying the structure, thus allowing the correct formation of the complex. A further hypothesis is the sequestration of stefin B by the multiprotein complex, thus impeding its interaction with cathepsins.
  

External links

Nomenclature
HGNC (Hugo)CSTB   2482
Cards
AtlasCSTBID40181ch21q22
Entrez_Gene (NCBI)CSTB  1476  cystatin B (stefin B)
GeneCards (Weizmann)CSTB
Ensembl (Hinxton) [Gene_View]  chr21:45193546-45196256 [Contig_View]  CSTB [Vega]
AceView (NCBI)CSTB
Genatlas (Paris)CSTB
WikiGenes1476
SOURCE (Princeton)NM_000100
Genomic and cartography
GoldenPath (UCSC)CSTB  -  21q22.3   chr21:45193546-45196256 -  21q22.3   [Description]    (hg19-Feb_2009)
EnsemblCSTB - 21q22.3 [CytoView]
Mapping of homologs : NCBICSTB [Mapview]
OMIM254800   601145   
Gene and transcription
Genbank (Entrez)AK312133 BC003370 BC010532 BT007040 BX419549
RefSeq transcript (Entrez)NM_000100
RefSeq genomic (Entrez)AC_000153 NC_000021 NC_018932 NG_011545 NT_011515 NW_001838716 NW_004929427
Consensus coding sequences : CCDS (NCBI)CSTB
Cluster EST : UnigeneHs.695 [ NCBI ]
CGAP (NCI)Hs.695
Alternative Splicing : Fast-db (Paris)GSHG0019747
Gene ExpressionCSTB [ NCBI-GEO ]     CSTB [ SEEK ]   CSTB [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP04080 (Uniprot)
NextProtP04080  [Medical]
With graphics : InterProP04080
Splice isoforms : SwissVarP04080 (Swissvar)
Domaine pattern : Prosite (Expaxy)CYSTATIN (PS00287)   
Domains : Interpro (EBI)Prot_inh_cystat    Prot_inh_cystat_CS    Prot_inh_stefinA   
Related proteins : CluSTrP04080
Domain families : Pfam (Sanger)Cystatin (PF00031)   
Domain families : Pfam (NCBI)pfam00031   
Domain families : Smart (EMBL)CY (SM00043)  
DMDM Disease mutations1476
Blocks (Seattle)P04080
PDB (SRS)1STF    2OCT   
PDB (PDBSum)1STF    2OCT   
PDB (IMB)1STF    2OCT   
PDB (RSDB)1STF    2OCT   
Peptide AtlasP04080
HPRD03091
IPIIPI00021828   
Protein Interaction databases
DIP (DOE-UCLA)P04080
IntAct (EBI)P04080
BioGRIDCSTB
InParanoidP04080
Interologous Interaction database P04080
IntegromeDBCSTB
STRING (EMBL)CSTB
Ontologies - Pathways
Ontology : AmiGOprotease binding  endopeptidase inhibitor activity  cysteine-type endopeptidase inhibitor activity  nucleolus  cytoplasm  adult locomotory behavior  negative regulation of peptidase activity  negative regulation of endopeptidase activity  regulation of apoptotic process  
Ontology : EGO-EBIprotease binding  endopeptidase inhibitor activity  cysteine-type endopeptidase inhibitor activity  nucleolus  cytoplasm  adult locomotory behavior  negative regulation of peptidase activity  negative regulation of endopeptidase activity  regulation of apoptotic process  
REACTOMECSTB
Protein Interaction DatabaseCSTB
Wikipedia pathwaysCSTB
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)CSTB
SNP (GeneSNP Utah)CSTB
SNP : HGBaseCSTB
Genetic variants : HAPMAPCSTB
1000_GenomesCSTB 
Somatic Mutations in Cancer : COSMICCSTB 
CONAN: Copy Number AnalysisCSTB 
Mutations and Diseases : HGMDCSTB
OMIM254800    601145   
GENETestsCSTB
Disease Genetic AssociationCSTB
Huge Navigator CSTB [HugePedia]  CSTB [HugeCancerGEM]
Genomic VariantsCSTB  CSTB [DGVbeta]
Exome VariantCSTB
dbVarCSTB
ClinVarCSTB
snp3D : Map Gene to Disease1476
General knowledge
Homologs : HomoloGeneCSTB
Homology/Alignments : Family Browser (UCSC)CSTB
Phylogenetic Trees/Animal Genes : TreeFamCSTB
Chemical/Protein Interactions : CTD1476
Chemical/Pharm GKB GenePA26984
Clinical trialCSTB
Other databases
Probes
Litterature
PubMed74 Pubmed reference(s) in Entrez
CoreMineCSTB
iHOPCSTB

Bibliography

Amino acid sequence of the intracellular cysteine proteinase inhibitor cystatin B from human liver.
Ritonja A, Machleidt W, Barrett AJ.
Biochem Biophys Res Commun. 1985 Sep 30;131(3):1187-92.
PMID 3902020
 
Isolation and characterization of the mouse cystatin B gene.
Pennacchio LA, Myers RM.
Genome Res. 1996 Nov;6(11):1103-9.
PMID 8938434
 
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
 
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
 
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 cathepsins (proteases)--on the main stage of cancer?
Turk V, Kos J, Turk B.
Cancer Cell. 2004 May;5(5):409-10.
PMID 15144947
 
Towards novel anti-cancer strategies based on cystatin function.
Keppler D.
Cancer Lett. 2006 Apr 28;235(2):159-76.
PMID 15893421
 
Cystatin B: mutation detection, alternative splicing and expression in progressive myclonus epilepsy of Unverricht-Lundborg type (EPM1) patients.
Joensuu T, Kuronen M, Alakurtti K, Tegelberg S, Hakala P, Aalto A, Huopaniemi L, Aula N, Michellucci R, Eriksson K, Lehesjoki AE.
Eur J Hum Genet. 2007 Feb;15(2):185-93. Epub 2006 Sep 27.
PMID 17003839
 
Cystatin B and its EPM1 mutants are polymeric and aggregate prone in vivo.
Cipollini E, Riccio M, Di Giaimo R, Dal Piaz F, Pulice G, Catania S, Caldarelli I, Dembic M, Santi S, Melli M.
Biochim Biophys Acta. 2008 Feb;1783(2):312-22. Epub 2007 Sep 4.
PMID 17920138
 
Identification of cystatin B as a potential serum marker in hepatocellular carcinoma.
Lee MJ, Yu GR, Park SH, Cho BH, Ahn JS, Park HJ, Song EY, Kim DG.
Clin Cancer Res. 2008 Feb 15;14(4):1080-9.
PMID 18281540
 
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Contributor(s)

Written07-2008Zala Jevnikar, Janko Kos
Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia

Citation

This paper should be referenced as such :
Jevnikar Z, Kos J . CSTB (cystatin B (stefin B)). Atlas Genet Cytogenet Oncol Haematol. July 2008 .
URL : http://AtlasGeneticsOncology.org/Genes/CSTBID40181ch21q22.html

The various updated versions of this paper are referenced and archived by INIST as such :
http://documents.irevues.inist.fr/bitstream/2042/44486/1/07-2008-CSTBID40181ch21q22.pdf   [ Bibliographic record ]

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indexed on : Fri Apr 18 17:28:21 CEST 2014

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