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CST6 (cystatin E/M)

Written2009-07Daniel Keppler
Department of Biological Sciences, College of Pharmacy, Touro University of California, 1310 Johnson Lane, Mare Island, Vallejo, CA 94592, USA

(Note : for Links provided by Atlas : click)

Identity

Other aliasCystatin-6
Cystatin-E
Cystatin M
Cystatin E/M
HGNC (Hugo) CST6
LocusID (NCBI) 1474
Atlas_Id 40178
Location 11q13.1  [Link to chromosome band 11q13]
Location_base_pair Starts at 66011991 and ends at 66013505 bp from pter ( according to hg19-Feb_2009)  [Mapping CST6.png]
Local_order The human CST6 gene is located on the long arm of chromosome 11 at 11q13.1. It corresponds to a total DNA sequence of about 1,515 bp. Most other human cystatin genes (i.e., the genes for CST1 to CST9 and CST11) cluster on chromosome 20p11.
 
  Figure 1: In the above diagram are represented the various genes flanking the human CST6 gene. More information on these genes can be found at: Entrez Gene.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
Note Misleading annotations:
-CSTB or CSTb (is a different cystatin gene)
-Yeast CST6 (is an unrelated gene encoding a yeast transcription factor)
-Mouse cystatin E1 (mouse CRES-like)
-Mouse cystatin E2 (mouse testatin-like)

DNA/RNA

Note The human CST6 gene is a tiny gene. Together with its basic promoter, it spans about 2,500 bp and is flanked in the 5' upstream region by an inverted, 290-bp Alu-Sx(Sq) repeat.
 
  Figure 2: Structure of the human CST6 gene. Exon-1 contains the 5'-UTR (in blue) and the starting ATG codon of the coding sequence (in magenta). Exon-3 contains a TGA stop codon and the 3'-UTR (in blue). More information on the CST6 gene organization can be found at: Entrez Gene.
Description Like most cystatin genes, the human CST6 gene is organized into three exons separated by two introns. Exon-1 is 294-bp long, contains the 5'-untranslated region (5'-UTR) and the starting ATG codon of the coding sequence. Exon-2 is 126-bp long. Exon-3 is 188-bp long, contains a TGA stop codon, the 3'-UTR as well as a typical AATAAA polyadenylation signal followed by 20 bp. Intron-1 and intron-2 are 541- and 365-bp in length, respectively.
Transcription The human CST6 gene is transcribed into a single mRNA species of about 607 nucleotides (nt). There are no alternate transcript species. The transcript is composed of a 5'-UTR of 53 nt, a coding sequence of 447 nt, and a 3'-UTR of 107 nt. A palyndromic structure located some 360 nt downstream of the AUG initiation codon (or 26 codons upstream of the TGA stop codon) seems to be responsible for some sequence variation in that region. Indeed, several expressed sequence tags (ESTs) differ primarily if not solely in that region of the mRNA sequence.
Transcription from the CST6 gene promoter seems to be both constitutive and regulated. Numerous potential SP1 binding sites (TESS/TransFac database v4.0) in the CST6 promoter may account for a low to moderate basal promoter activity in many tissues. High expression occurs only in a few tissues such as the skin, placenta, ovary, pancreas and the lungs. A quite widespread expression of CST6 is also supported by data extracted from gene expression libraries (GEO, GeneNote, GNF Symatlas, CGAP, EST, SAGE, and UniGene eNortherns). However, there are some conflicting data in the literature suggesting that the CST6 mRNA is expressed in a tissue-specific manner mainly if not exclusively in the skin.
Expression from the human CST6 gene is epigenetically silenced in several tumor types (see below). The 5'-end of the CST6 gene including exon-1 has an unusually high (≥ 70%) content in G and C nucleotides. As a matter of fact, a typical CpG island spans across the transcription start site (bp +1) from bp -186 to bp +320 and encompasses all of exon-1. Not surprisingly, treatment of tumor cells by histone deacetylase or DNA methyltransferase inhibitors results in 're-expression' of CST6 at levels similar to those seen in the normal or benign counterparts.
The unusual GC content (~ 80%) of the 5'-UTR of the mRNA suggests that CST6 expression might also be regulated at the translational level by eIF-4E.
Pseudogene No pseudogenes have been identified.

Protein

Note The CST6 gene product, Cst6, is a typical secretory protein. It is synthesized as a preprotein with a patent N-terminal signal sequence. The protein is translocated into the rough endoplasmic reticulum where about 30-50% of the nascent Cst6 polypeptides are N-glycosylated. Upon SDS-PAGE, Cst6 harvested from most cell secretions migrates as two major forms, a 14-kDa unglycosylated and a 17- to 18-kDa glycosylated form.
Description The three-dimensional organization of Cst6 (assuming it is similar to that of chicken egg white cystatin shown in figure 4) is that of a compact five-pleated beta-sheet that partially wraps around a central alpha-helix. It is not clear what role glycosylation of residue N137 fulfills. Perhaps, N-glycosylation promotes binding of the protein to cells and entry into the endosomal/lysosomal system where Cst6 can interact with target proteases.
 
  Figure 3: The above diagram depicts the primary structure of the Cst6 precursor. The first 28 amino acids represent a canonical signal peptide. The mature and secreted Cst6 molecule (in blue) contains two disulfide bonds (-S-S-), one N-glycosylation site (N137-CHO), and two distinct binding sites for lysosomal cysteine proteases (purple and yellow boxes). The purple boxes represent the amino acids (RMVG, QLVAG and PW) that are involved in the binding and inhibition of the cathepsins B, K, L, L2/V or S. The yellow box represents the critical amino acid (N64) for binding and inhibition of lysosomal Asn-endopeptidase (AEP or mammalian legumain).
Figure 4: Typical crystal structure of a secretory cystatin. The coordinates for the crystal structure of chicken egg white cystatin (1CEW) were obtained from the PDB database. A 3D-model of the cystatin was then generated using SwissPDB-Viewer. The N- and C-termini of the protein are marked by 'N' and 'C', respectively. The two conserved disulfide bonds are highlighted in yellow. The amino acids that are part of the two distinct binding sites for lysosomal cysteine proteases are labeled by purple and yellow boxes as described in the legend to figure 3. N64 and W135 are particularly important in this regard and are highlighted in blue. The amino acid numbering refers to that of the Cst6 preprotein, i.e., the protein with a 28-amino acid signal peptide (not present).
Expression Cst6 is a cell-secreted protein. In vitro, the majority (> 95%) of the protein accumulates in the media conditioned by the cells. In cells that overexpress Cst6, prominent labeling of the Golgi apparatus can be seen using indirect immunofluorescence cytochemistry.
Localisation In the human skin, where localisation of Cst6 has been most carefully explored, the protein is detected in the stratum granulosum of the epidermis, in the outer root sheet of hair follicles, in the secretory coil epithelium of sweat glands, and in the inner, mature cells of sebaceous glands.
Function Protease Inhibitor Function: The most widely accepted function of cystatins is that of protease inhibitors. The name 'cystatin' further reminds us that these endogenous protease inhibitors target cysteine proteases. In contrast to metallo- and serine proteases that are mostly secreted proteases, most cysteine proteases are confined within cells where optimal pH and redox conditions favor their enzymatic activity. Thus, the majority of intracellular cysteine proteases are inactivated by oxidizing conditions outside the cells. Nevertheless, it is believed that cystatins inhibit cysteine proteases much faster than do oxidizing conditions and, thereby, prevent excessive tissue damage during the release of lysosomal enzymes.
Among the various types of intracellular cysteine proteases, cystatins seem to target preferentially endosomal/lysosomal cysteine proteases of the papain family, such as cathepsin B, cathepsin K/O2, cathepsin L, cathepsin L2/V and cathepsin S. Some cystatins such as Cst6 are double-headed inhibitors and have a second inhibitory site, i.e., N64 in figures 3 and 4 above. Via this alternate inhibitory site, Cst6 is capable of binding and inhibiting legumain-type cysteine proteases such as AEP/mammalian legumain. Cystatins do not inhibit caspases and calpains seem to be regulated in a different manner. Little is known about the inhibitory potential of cystatins towards other types of intracellular cysteine proteases.
Epithelial barrier function: One important function of Cst6 seems to be in the terminal differentiation of stratified squamous epithelial cells and in the formation of cornified envelops. Indeed, ichq mice with a null mutation in the cst6 gene develop neonatal abnormalities in skin cornification and desquamation that resemble Harlequin ichthyoses in humans. However, no alterations in the CST6 gene were found in the DNA of patients with Harlequin ichthyosis. In mice, the lack of Cst6 function leads to severe dehydration and neonatal lethality. Before serving as a substrate to transglutaminases and being deposited into cornified cell envelops, Cst6 is believed to be important in fine-tuning the enzymatic activities of endosomal/lysosomal cysteine proteases such as cathepsin L, cathepsin L2/V and AEP/mammalian legumain. Deregulated activity of these proteases could lead to abnormal activation of transglutaminases and disorders in cornification.
Homology CST6 Gene orthologs:
SpeciesUniGene IDChromosomeHomology
Human
Hs.139389
11q13.1
100%/149 aa
Pig
Ssc.9061
2p16-17
78%/149 aa
Cow
Bt.5468
29
75%/148 aa
Dog
Cfa.23670
18
71%/149 aa
Rat
Rn.9609
1q43
70%/149 aa
Mouse
Mm.36816
19 A (4.0 cM)
69%/149 aa
Worm
Cel.5518
V
13%/143 aa
 

Mutations

Note In 2004, CST6 was coined as a novel candidate tumor suppressor gene for breast carcinoma. Since then, this gene has been identified as a tumor suppressor gene for other cancers such as cancers of the breast, prostate, brain, lung, cervix and melanocytes. In most tumor tissues, CST6 seems to be epigenetically silenced rather than deleted or mutated. However, in one case (see below) more profound alterations in the human CST6 gene have been observed.
Cervical cancer: One out of 19 primary tumors revealed homozygous deletion of exon-1 sequences. Six other primary tumors exhibited point mutations in the CDS of the CST6 gene. Two of these mutations (M34T and L131F) occurred in proximity to the consensus binding sites for cathepsins (figure 6) and resulted in diminished affinity of the mutant inhibitor for cathepsin L.
 
  Figure 6: This diagram depicts locations of six point mutations and one deletion affecting the CST6 gene that have been observed in cancer specimens. Amino acid numbering refers to the precystatin sequence as for figure 3.
Germinal No germ-line mutations have been detected.

Implicated in

Note
Note Cancer progression
Loss of heterozygosity (LOH) affecting the locus 11q13 is quite common in cancers. This locus indeed harbors several tumor or metastasis suppressor genes such as BAD, MEN1, BRMS1, RASGRP2, GSTP1 and CST6.
In a study using differential RNA display it was initially established that human breast cancer cell lines exhibited lack or reduced CST6 expression when compared to immortal or normal counterparts. CST6 was coined a novel candidate tumor suppressor gene for breast cancer on October 1st, 2004. Since then, several groups have reported on the lack or diminished expression of CST6 in various cancer types (listed below). However, some groups also observed overexpression of CST6 in select cancer types (listed below). One of the challenges in current research on CST6 is to define the proteases targeted by CST6 and their precise role in the progression of the disease.
  
Note Cancer types with diminished CST6 expression
  
  
Entity Breast cancer
Note Using various approaches, several groups have independently established that the human CST6 gene promoter is epigenetically silenced in breast carcinomas when compared to normal breast tissue. In one study, 24/40 (60%) breast carcinomas exhibited CST6 promoter hypermethylation as compared to 7/28 (25%) normal breast tissue samples. In another study, 25/45 (56%) of primary tumors and 17/20 (85%) of lymph node metastases expressed reduced levels of CST6 when compared to normal breast tissues. CST6 promoter hypermethylation could be demonstrated in 3/11 (27%) primary tumors and 8/12 (67%) lymph node metastases. In 35% of neoplastic lesions, no association could be established between the loss of CST6 expression and promoter methylation. This suggests that besides promoter hypermethylation other (structural or regulatory) mechanisms might operate to prevent CST6 expression in cancer cells.
Most established breast cancer cell lines also exhibited little or no CST6 expression (21MT-1, MCF-7, T-47D, ZR-75-1, Hs578T, SK-BR-3, MDA-MB-157, MDA-MB-361, MDA-MB-435S, MDA-MB-436, MDA-MB-453, BT-474 and BT-549). Some established breast cancer cell lines expressed moderate levels of CST6 (MDA-MB-231, MDA-MB-415 and MDA-MB-468) and only few (21PT, 21NT, 21MT-2 and BT-20) expressed levels of CST6 similar to normal or immortal counterparts (70N and 80N or 76N, MCF-10A, MCF-10AT and MCF-12A, respectively). Treatment of CST6-negative tumor cells by the histone deacetylase inhibitor Trichostatin A (TSA) or the DNA methyltransferase inhibitor 5-Aza-2'-deoxycytidine (5-Aza) results in 're-expression' of CST6 at levels similar to those seen in the normal or benign counterparts.
Overexpression of CST6 in breast cancer cells (MDA-MB-435S and T-47D) is associated with diminished tumor cell colony formation, proliferation, migration, Matrigel invasion and orthotopic tumor growth in scid mice.
  
  
Entity Prostate cancer
Note In a study of matched pairs of normal/cancer tissues, loss of CST6 expression was observed in 18/20 (90%) prostate cancers. Similarly, only 6% of prostate cancers exhibited strong Cst6 immunohistochemical staining as compared to 63% of normal tissues.
Among prostate cancer cell lines, RWPE-1 and DU-145 express high and moderate levels of CST6, respectively, whereas LNCaP, PC-3 and PC-3M express little to no CST6. Treatment with TSA leads to strong upregulation of CST6 expression in all three cell lines. In contrast, treatment with 5-Aza up to five days had no effect. Further studies using methylation-specific PCR showed that prostate cancer cell lines and tissues had lower promoter methylation than normal tissues. DNA hypermethylation of the CST6 promoter does therefore not account for the silencing of CST6 expression in prostate cancer. Instead, histone deacetylation and chromatin remodeling seem to be responsible for diminished CST6 expression.
Similar to breast cancer cells, forced expression of CST6 in prostate cancer cells (PC-3) leads to diminished tumor cell proliferation and Matrigel invasion. In addition, overexpression of CST6 also selectively reduces expression of the target enzyme, cathepsin B. Conversely, silencing of CST6 expression in a CST6-positive prostate cancer cell line (RWPE-1) leads to the exact opposite results from overexpression. In mice, orthotopic injection of PC-3 cells overexpressing CST6 resulted in considerably smaller tumors when compared to vector controls. The CST6 tumors expressed reduced levels of cathepsin B.
  
  
Entity Lung cancer
Note Two groups have recently reported on the epigenetic silencing of the CST6 gene in non-small cell lung cancer (NSCLC) using genome-wide expression profiling. In one study, 2/5 (40%) primary tumors and 1/5 (20%) normal lung tissues exhibited CST6 promoter methylation. In the other study, the numbers were respectively 10/19 (53%) and 2/15 (13%).
NSCLC cell lines that express little or no CST6 are the following: A-427, A-549, NCI-H23, NCI-H522, NCI-H1299 and NCI-H460. Three cell lines expressed moderate to high levels of CST6 (NCI-H322, NCI-H358 and NCI-H292). In all nine above cell lines, CST6 expression could be increased to normal levels by a combined treatment of the cells with TSA and 5-Aza.
Overexpression of CST6 in lung adenocarcinoma A-549 cells resulted in a > 50% reduction in colony formation in vitro compared to vector controls.
  
  
Entity Cervical cancer
Note One study recently reported on the lack of CST6 expression in 9/11 (82%) primary squamous cell carcinomas of the cervix, but expression of the gene in 5/5 (100%) normal cervical tissues as well as in normal lung, thyroid, kidney, brain, ovary, uterus, smooth muscle and connective tissues. Two out of 11 (18%) primary tumors (one of which being an adenocarcinoma) expressed low levels of CST6, which might be due to contamination of the tumor material by adjacent normal tissue.
Cervical cancer cell lines such as HeLa (D98/AH-2), C41, SiHa, Caski, HT3 and C33A all lack expression of CST6. Treatment of tumor cells by 5-Aza and/or TSA results in 're-expression' of CST6 at levels similar to those seen in normal tissues. Similar to the situation in prostate cancer cells, some cell lines (SiHa and HT3) respond only to TSA treatment. Caski, C33A and C41 cells exhibit both unmethylated and hypermethylated CST6 promoters whereas HeLa cells has homogenously hypermethylated CST6 promoters.
Overexpression of CST6 in HeLa and SiHa cells leads in both cases to a reduction in the number and size of colonies forming in soft agar and in cell proliferation. Another consequence of the forced expression of CST6 in HeLa cells is a reduction in intracellular levels of the target protease, cathepsin L, possibly explaining the reduced growth of the CST6 overexpressing cells.
  
  
Entity Head and neck squamous cell carcinoma (HNSCC)
Note Comparison of the gene expression profiles (HuFL6800) of two matched pairs of primary and metastatic human oropharyngeal SCC cell lines (MDA-686TU and LN) revealed relative overexpression of CST6 in the metastatic cell line. Immuno-cytochemical analysis further showed that overexpression of CST6 in the metastatic cell line was not homogenous. Instead, small clusters of cells overexpressed the protein whereas the majority of cells expressed little or no CST6. Further studies using RNA interference indicated that loss of CST6 expression in MDA-686LN promoted proliferation of the cells and Matrigel invasion.
In another study, human SCC-25 cells were treated with the vitamin D3 analog EB1089 for various times and the effect of this drug treatment on gene expression analyzed using HuGene FL oligo microarrays. In this study, CST6 expression was found to increase > 30-fold over a 24-hr period. Overall, EB1089 treatment reversed the malignant phenotype of SCC-25 cells and induced keratinocytic differentiation.
  
  
Entity Brain cancer
Note One study reported on downregulation of CST6 expression in 15/17 (88%) brain tumors, which included 7/9 (78%) multiform glioblastomas (MG). Moreover, MSP analysis demonstrated CST6 promoter methylation in 17/30 (57%) brain tumors. These latter included 14/19 (74%) MGs. In comparison to brain tumors, normal brain tissue exhibited only 6% CST6 promoter methylation.
CST6 expression and methylation status was also analyzed in six glioblastoma cell lines: LN-229, LN-18, T98G, DBTRG-05MG, U-87MG and U-118MG. All six cell lines expressed little or no CST6. In addition, all cell lines had quite homogenously hypermethylated CST6 promoters. Re-expression of CST6 could be triggered with 5-Aza alone.
Transfection of T98G, LN-229 and U-87MG cells with a mammalian CST6 expression vector resulted in a modest (20-25%) suppression of T98G and LN-229 cell growth when compared to vector controls. Forced expression of CST6 in U-87MG cells had no effect on their capacity to form colonies and proliferate.
In conclusion, CST6-mediated suppression of tumor cell growth seems to be most pronounced in cells of epithelial origin, i.e., in cells developing multiple cell-to-cell communications and elaborating a basement membrane.
  
Note Cancer types with increased CST6 expression
  
  
Entity Squamous cell carcinoma of the skin
Note Squamous cell carcinoma (SCC) of the skin versus psoriasis.
CST6 is highly expressed in the normal human skin, which might explain why no further increase in expression could be detected in SCC. However, a five- to six-fold differential expression of CST6 was observed when SCC was compared to psoriatic skin. Differential expression of CST6 was accompanied by a similar differential expression of one of its target proteases, cathepsin L2/V.
  
  
Entity Pancreatic cancer
Note CST6 was identified as an upregulated gene in several genome-wide expression studies. One study used microarray analysis to profile gene expression in pancreatic adenocarcinomas (T=10), pancreatic cancer cell lines (C=7), chronic pancreatitis (P=5) and normal pancreas (N=5). According to this study, CST6 levels change 20-, 20- and 24-fold in T/N, T/P and C/N, respectively. In another study using a similar approach (oligo microarray) the T/N ratio was found to be 4.4-fold and upregulation of CST6 was not observed using other platforms such as SAGE or cDNA-based microarrays. Instead, among six genes that were consistently overexpressed across all three platforms was one of the major CST6 targets, cathepsin L2/V.
In yet another study using a cDNA microarray, CST6 was found to be overexpressed in 18 microdissected pancreatic ductal adenocarcinomas (PDAC) when compared to normal ductal epithelial cells. Subsequent silencing of CST6 expression in a PDAC cell line (PK-59) reduced colony formation and cell proliferation. Conversely, overexpression of CST6 in a CST6-negative PDAC cell line (KLM-1) promoted tumor growth in nude mice. Likewise, addition of recombinant human CST6 to the growth medium of KLM-1 cells promoted their proliferation in a dose-dependent manner. Engineered CST6 variants lacking either N-glycosylation (N137D, figure 3) or with an altered protease binding site (deletion of MVG38, figures 3 & 4) did not have any effect on cell proliferation suggesting that both N-glycosylation and protease specificity are required for oncogenic activity of CST6.
  
  
Entity Thyroid cancer
Note Initial immunohistochemical studies found positive staining for CST6 in 80% (8/10) of papillary thyroid carcinomas (PTC) and 73% (11/15) of benign thyroid lesions. Independent studies established a strong correlation between CST6 expression, PTC and BRAF (V600E) mutational status. CST6 expression was also associated with PTC lymph node metastasis.
  
  
Entity Ovarian cancer (OvCA)
Note In order to better define the molecular profiles of the four major histological types of OvCAs (clear cell, mucinous, endometrioid, and serous), a microarray analysis was performed on 113 human specimens. Expression of CST6 was found to be on average 3.8-fold higher in clear cell OvCAs when compared to other histological types. It is interesting to note here that more than one-half of clear cell OvCAs do not exhibit tumor invasion at presentation.
  

Breakpoints

Note A 300-kb region flanked by the markers D11S4908 and D11S5023 and harboring the CST6 gene has been identified as the minimal tumor deletion on 11q13 in cervical cancer cell lines and primary cervical tumors. This region was reported to contain a high density of DNA repeats rendering it fragile and prone to potential DNA breaks and carcinogenesis. A rare fragile site FRA11A overlaps indeed with this region.

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Pulukuri SM, Gorantla B, Knost JA, Rao JS.
Oncogene. 2009 Jun 8. [Epub ahead of print]
PMID 19503093
 
Invasion suppressor cystatin E/M (CST6): high-level cell type-specific expression in normal brain and epigenetic silencing in gliomas.
Qiu J, Ai L, Ramachandran C, Yao B, Gopalakrishnan S, Fields CR, Delmas AL, Dyer LM, Melnick SJ, Yachnis AT, Schwartz PH, Fine HA, Brown KD, Robertson KD.
Lab Invest. 2008 Sep;88(9):910-25. Epub 2008 Jul 7.
PMID 18607344
 
Methylation profiles of 22 candidate genes in breast cancer using high-throughput MALDI-TOF mass array.
Radpour R, Kohler C, Haghighi MM, Fan AX, Holzgreve W, Zhong XY.
Oncogene. 2009 Jun 8. [Epub ahead of print]
PMID 19503099
 
Epigenetic regulation of cystatins in cancer.
Rivenbark AG, Coleman WB.
Front Biosci. 2009 Jan 1;14:453-62. (REVIEW)
PMID 19273077
 
Epigenetic mapping and functional analysis in a breast cancer metastasis model using whole-genome promoter tiling microarrays.
Rodenhiser DI, Andrews J, Kennette W, Sadikovic B, Mendlowitz A, Tuck AB, Chambers AF.
Breast Cancer Res. 2008;10(4):R62. Epub 2008 Jul 18.
PMID 18638373
 
DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines.
Roll JD, Rivenbark AG, Jones WD, Coleman WB.
Mol Cancer. 2008 Jan 25;7:15.
PMID 18221536
 
Frequent epigenetic inactivation of cystatin M in breast carcinoma.
Schagdarsurengin U, Pfeifer GP, Dammann R.
Oncogene. 2007 May 10;26(21):3089-94. Epub 2006 Nov 13.
PMID 17099723
 
Gene expression in ovarian cancer reflects both morphology and biological behavior, distinguishing clear cell from other poor-prognosis ovarian carcinomas.
Schwartz DR, Kardia SL, Shedden KA, Kuick R, Michailidis G, Taylor JM, Misek DE, Wu R, Zhai Y, Darrah DM, Reed H, Ellenson LH, Giordano TJ, Fearon ER, Hanash SM, Cho KR.
Cancer Res. 2002 Aug 15;62(16):4722-9.
PMID 12183431
 
Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells.
Shridhar R, Zhang J, Song J, Booth BA, Kevil CG, Sotiropoulou G, Sloane BF, Keppler D.
Oncogene. 2004 Mar 18;23(12):2206-15.
PMID 14676833
 
The candidate tumor suppressor CST6 alters the gene expression profile of human breast carcinoma cells: down-regulation of the potent mitogenic, motogenic, and angiogenic factor autotaxin.
Song J, Jie C, Polk P, Shridhar R, Clair T, Zhang J, Yin L, Keppler D.
Biochem Biophys Res Commun. 2006 Feb 3;340(1):175-82. Epub 2005 Dec 9.
PMID 16356477
 
Identification, cloning, and characterization of cystatin M, a novel cysteine proteinase inhibitor, down-regulated in breast cancer.
Sotiropoulou G, Anisowicz A, Sager R.
J Biol Chem. 1997 Jan 10;272(2):903-10.
PMID 8995380
 
Assignment of a novel cysteine proteinase inhibitor (CST6) to 11q13 by fluorescence in situ hybridization.
Stenman G, Astrom AK, Roijer E, Sotiropoulou G, Zhang M, Sager R.
Cytogenet Cell Genet. 1997;76(1-2):45-6.
PMID 9154125
 
Inactivation of the cystatin E/M tumor suppressor gene in cervical cancer.
Veena MS, Lee G, Keppler D, Mendonca MS, Redpath JL, Stanbridge EJ, Wilczynski SP, Srivatsan ES.
Genes Chromosomes Cancer. 2008 Sep;47(9):740-54.
PMID 18506750
 
Silencing of cystatin M in metastatic oral cancer cell line MDA-686Ln by siRNA increases cysteine proteinases and legumain activities, cell proliferation and in vitro invasion.
Vigneswaran N, Wu J, Nagaraj N, James R, Zeeuwen P, Zacharias W.
Life Sci. 2006 Jan 18;78(8):898-907. Epub 2005 Sep 8.
PMID 16150465
 
Cystatins C, E/M and F in human pleural fluids of patients with neoplastic and inflammatory lung disorders.
Werle B, Sauckel K, Nathanson CM, Bjarnadottir M, Spiess E, Ebert W, Abrahamson M.
Biol Chem. 2003 Feb;384(2):281-7.
PMID 12675521
 
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PMID 16969475
 
The biology of cystatin M/E and its cognate target proteases.
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J Invest Dermatol. 2009 Jun;129(6):1327-38. Epub 2009 Mar 5. (REVIEW)
PMID 19262604
 
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Eur J Cell Biol. 2004 Dec;83(11-12):761-73. (REVIEW)
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Citation

This paper should be referenced as such :
Keppler, D
CST6 (cystatin E/M)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(6):538-546.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/CST6ID40178ch11q13.html


External links

Nomenclature
HGNC (Hugo)CST6   2478
Cards
AtlasCST6ID40178ch11q13
Entrez_Gene (NCBI)CST6  1474  cystatin E/M
Aliases
GeneCards (Weizmann)CST6
Ensembl hg19 (Hinxton)ENSG00000175315 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000175315 [Gene_View]  chr11:66011991-66013505 [Contig_View]  CST6 [Vega]
ICGC DataPortalENSG00000175315
TCGA cBioPortalCST6
AceView (NCBI)CST6
Genatlas (Paris)CST6
WikiGenes1474
SOURCE (Princeton)CST6
Genetics Home Reference (NIH)CST6
Genomic and cartography
GoldenPath hg38 (UCSC)CST6  -     chr11:66011991-66013505 +  11q13.1   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)CST6  -     11q13.1   [Description]    (hg19-Feb_2009)
EnsemblCST6 - 11q13.1 [CytoView hg19]  CST6 - 11q13.1 [CytoView hg38]
Mapping of homologs : NCBICST6 [Mapview hg19]  CST6 [Mapview hg38]
OMIM601891   
Gene and transcription
Genbank (Entrez)AA778147 AI127639 AK092391 BC031334 CR456872
RefSeq transcript (Entrez)NM_001323
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)CST6
Cluster EST : UnigeneHs.139389 [ NCBI ]
CGAP (NCI)Hs.139389
Alternative Splicing GalleryENSG00000175315
Gene ExpressionCST6 [ NCBI-GEO ]   CST6 [ EBI - ARRAY_EXPRESS ]   CST6 [ SEEK ]   CST6 [ MEM ]
Gene Expression Viewer (FireBrowse)CST6 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevisibleExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)1474
GTEX Portal (Tissue expression)CST6
Human Protein AtlasENSG00000175315-CST6 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ15828   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ15828  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ15828
Splice isoforms : SwissVarQ15828
PhosPhoSitePlusQ15828
Domaine pattern : Prosite (Expaxy)CYSTATIN (PS00287)   
Domains : Interpro (EBI)Cystatin    Cystatin_dom    Prot_inh_cystat_CS   
Domain families : Pfam (Sanger)Cystatin (PF00031)   
Domain families : Pfam (NCBI)pfam00031   
Domain families : Smart (EMBL)CY (SM00043)  
Conserved Domain (NCBI)CST6
DMDM Disease mutations1474
Blocks (Seattle)CST6
PDB (SRS)4N6L    4N6M    4N6N    4N6O   
PDB (PDBSum)4N6L    4N6M    4N6N    4N6O   
PDB (IMB)4N6L    4N6M    4N6N    4N6O   
PDB (RSDB)4N6L    4N6M    4N6N    4N6O   
Structural Biology KnowledgeBase4N6L    4N6M    4N6N    4N6O   
SCOP (Structural Classification of Proteins)4N6L    4N6M    4N6N    4N6O   
CATH (Classification of proteins structures)4N6L    4N6M    4N6N    4N6O   
SuperfamilyQ15828
Human Protein Atlas [tissue]ENSG00000175315-CST6 [tissue]
Peptide AtlasQ15828
HPRD03535
IPIIPI00019954   
Protein Interaction databases
DIP (DOE-UCLA)Q15828
IntAct (EBI)Q15828
FunCoupENSG00000175315
BioGRIDCST6
STRING (EMBL)CST6
ZODIACCST6
Ontologies - Pathways
QuickGOQ15828
Ontology : AmiGOcornified envelope  cysteine-type endopeptidase inhibitor activity  epidermis development  anatomical structure morphogenesis  negative regulation of endopeptidase activity  extracellular exosome  
Ontology : EGO-EBIcornified envelope  cysteine-type endopeptidase inhibitor activity  epidermis development  anatomical structure morphogenesis  negative regulation of endopeptidase activity  extracellular exosome  
NDEx NetworkCST6
Atlas of Cancer Signalling NetworkCST6
Wikipedia pathwaysCST6
Orthology - Evolution
OrthoDB1474
GeneTree (enSembl)ENSG00000175315
Phylogenetic Trees/Animal Genes : TreeFamCST6
HOVERGENQ15828
HOGENOMQ15828
Homologs : HomoloGeneCST6
Homology/Alignments : Family Browser (UCSC)CST6
Gene fusions - Rearrangements
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerCST6 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)CST6
dbVarCST6
ClinVarCST6
1000_GenomesCST6 
Exome Variant ServerCST6
ExAC (Exome Aggregation Consortium)ENSG00000175315
GNOMAD BrowserENSG00000175315
Genetic variants : HAPMAP1474
Genomic Variants (DGV)CST6 [DGVbeta]
DECIPHERCST6 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisCST6 
Mutations
ICGC Data PortalCST6 
TCGA Data PortalCST6 
Broad Tumor PortalCST6
OASIS PortalCST6 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICCST6  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDCST6
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 CST6
DgiDB (Drug Gene Interaction Database)CST6
DoCM (Curated mutations)CST6 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)CST6 (select a term)
intoGenCST6
NCG5 (London)CST6
Cancer3DCST6(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM601891   
Orphanet
MedgenCST6
Genetic Testing Registry CST6
NextProtQ15828 [Medical]
TSGene1474
GENETestsCST6
Target ValidationCST6
Huge Navigator CST6 [HugePedia]
snp3D : Map Gene to Disease1474
BioCentury BCIQCST6
ClinGenCST6
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD1474
Chemical/Pharm GKB GenePA26979
Clinical trialCST6
Miscellaneous
canSAR (ICR)CST6 (select the gene name)
Probes
Litterature
PubMed43 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineCST6
EVEXCST6
GoPubMedCST6
iHOPCST6
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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