Cystatin M/E Expression is Restricted to Differentiated Epidermal Keratinocytes and Sweat Glands: a New Skin-Specific Proteinase Inhibitor that is a Target for Cross-Linking by Transglutaminase

Zeeuwen, Patrick L.J.M.; Vlijmen-Willems, Ivonne M.J.J. van; Jansen, Bas; Sotiropoulou, Georgia; Curfs, J.H.A.J.; Meis, Jacques F.; Janssen, J.J.M.; Ruissen, Fred van; Schalkwijk, Joost

doi:10.1046/j.1523-1747.2001.01309.x

Cited by 96 publications

(105 citation statements)

References 61 publications

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“…5B) and other methylation-negative tumors ( Supplementary Fig. S3), we observed intense staining of normal ductal epithelium within the surgical margin of this tumor, in clear agreement with the epithelial expression pattern observed previously for cystatin M (46,47). We also observed strong staining of both DCIS and IBC lesions within the tumor mass, consistent with the lack of gene methylation observed in this tumor sample.…”

Section: Resultssupporting

confidence: 91%

Epigenetic Silencing of the Tumor Suppressor Cystatin M Occurs during Breast Cancer Progression

Kim

et al. 2006

Cancer Research

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Cystatin M is a secreted inhibitor of lysosomal cysteine proteases. Several lines of evidence indicate that cystatin M is a tumor suppressor important in breast malignancy; however, the mechanism(s) that leads to inactivation of cystatin M during cancer progression is unknown. Inspection of the human cystatin M locus uncovered a large and dense CpG island within the 5 ¶ region of this gene (termed CST6). Analysis of cultured human breast tumor lines indicated that cystatin M expression is either undetectable or in low abundance in several lines; however, enhanced gene expression was measured in cells cultured on the DNA demethylating agent 5-aza-2 ¶-deoxycytidine (5-aza-dC). Increased cystatin M expression does not correlate with a cytotoxic response to 5-aza-dC; rather, various molecular approaches indicated that the CST6 gene was aberrantly methylated in these tumor lines as well as in primary breast tumors. Moreover, 60% (12 of 20) of primary tumors analyzed displayed CST6 hypermethylation, indicating that this aberrant characteristic is common in breast malignancies. Finally, preinvasive and invasive breast tumor cells were microdissected from nine archival breast cancer specimens. Of the five tumors displaying CST6 gene methylation, four tumors displayed methylation in both ductal carcinoma in situ and invasive breast carcinoma lesions and reduced expression of cystatin M in these tumors was confirmed by immunohistochemistry. In summary, this study establishes that the tumor suppressor cystatin M is a novel target for epigenetic silencing during mammary tumorigenesis and that this aberrant event can occur before development of invasive breast cancer. (Cancer Res 2006; 66(16): 7899-909)

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Section: Resultssupporting

confidence: 91%

Epigenetic Silencing of the Tumor Suppressor Cystatin M Occurs during Breast Cancer Progression

Kim

et al. 2006

Cancer Research

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“…Alternatively, immunostaining of cystatin M in a subpopulation of cells that have metastasized suggests that the cystatin M gene might be re-expressed in oropharyngeal tumor cells that are undergoing differentiation at the secondary site. This would be in agreement with earlier studies showing that cystatin M is crosslinked to the stratum corneum during terminal differentiation of keratinocytes (Zeeuwen et al, 2001). Moreover, cystatin M expression was found to be increased 20-fold in human head and neck squamous carcinoma cells, upon induction of cell differentiation by the low calcemic vitamin D 3 analog EB1089 (Lin et al, 2002).…”

Section: Discussionsupporting

confidence: 93%

Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells

et al. 2003

Self Cite

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Proteases are involved in many aspects of tumor progression, including cell survival and proliferation, escape from immune surveillance, cell adhesion and migration, remodeling and invasion of the extracellular matrix. Several lysosomal cysteine proteases have been cloned and shown to be overexpressed in cancer; yet, despite the great potential for development of novel therapeutics, we still know little about the regulation of their proteolytic activity. Cystatins such as cystatin M are potent endogenous protein inhibitors of lysosomal cysteine proteases. Cystatin M is expressed in normal and premalignant human epithelial cells, but not in many cancer cell lines. Here, we examined the effects of cystatin M expression on malignant properties of human breast carcinoma MDA-MB-435S cells. Cystatin M was found to significantly reduce in vitro: cell proliferation, migration, Matrigel invasion, and adhesion to endothelial cells. Reduction of cell proliferation and adhesion to an endothelial cell monolayer were both independent of the inhibition of lysosomal cysteine proteases. In contrast, cell migration and matrix invasion seemed to rely on lysosomal cysteine proteases, as both recombinant cystatin M and E64 were able to block these processes. This study provides the first evidence that cystatin M may play important roles in safeguarding against human breast cancer.

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“…However, these two studies were not entirely consistent in the levels of expression in various tissues. Fully contradicting these studies, a CST6 gene-specific sensitive RT-PCR screen of a large number of human tissues-including gingiva, trachea, prostate, kidney, and mammary gland-failed to detect cystatin E/M anywhere except the skin (Zeeuwen et al, 2001). The protein was immunolocalized to the stratum granulosum of normal skin and secretory coils of eccrine sweat glands, and was expressed by epidermal keratinocytes in vitro.…”

Section: (3) Expression Of Non-sd-type Cystatin Genesmentioning

confidence: 98%

Salivary (SD-Type) Cystatins: Over One Billion Years in the Making—But to What Purpose?

Dickinson

2002

Critical Reviews in Oral Biology & Medicine

103

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The cystatin superfamily is comprised of a large group of ancestrally related proteins, most of which are potent inhibitors of cysteine peptidases (CPs). Human saliva contains relatively abundant proteins that are related ancestrally in sequence to the cystatin superfamily. These proteins are now commonly referred to as 'salivary cystatins', although this is something of a misnomer (see below). It has been several years since the publication of the last comprehensive reviews that focused on the salivary cystatins (Bobek and Levine, 1992;Henskens et al., 1996c). Since then, significant advances have been made regarding the gene organization, protein structure, and properties of human and rat proteins. Therefore, a major purpose of this article is to review this recent work. What is the function of the 'salivary cystatins'? Despite a great deal of research effort, we still do not have a definitive answer to this question. A major impediment is the lack of a disease to associate with a specific defect in a gene: Functionality must be inferred from circumstantial evidence. A central premise of this review is that clues to 'salivary cystatin' function are contained within their phylogenetic history, and that by looking at established or likely functions of their 'siblings' and 'cousins', one can assess the likelihood of this function(s) continuing into the 'salivary cystatins'. A comprehensive review of the large cystatin superfamily is beyond the scope of a single article. This review will aim to outline the main branches of the superfamily and the common elements of their structure and function, but will pay closest attention to the nearest relatives of the 'salivary cystatins'.(1) BACKGROUND Scission of peptide bonds is an essential reaction in living cells, and there is a considerable number of peptidases that catalyze this reaction with various degrees of specificity. CPs use a cysteine residue in the active site as the nucleophile in the reaction (see Dickinson, 2002, and references therein). Release of proteolytic enzymes outside of their normal compartment has the potential to cause serious degradation and pathology-an effect taken advantage of by pathogenic organisms from a wide range of phyla. Therefore, control of proteolytic enzyme activity is mandatory. Building upon a very early report (see Barrett et al., 1986, for a review of this earlier literature) of a bovine trypsin inhibitor in chicken egg white, a search for egg white inhibitors of plant proteinases (the CPs ficin and papain) identified a relatively small (12.7 kDa) protein that was a potent inhibitor (Ki = 10 nM). The term cystatin was coined for this protein, which was shown also to inhibit mammalian CPs of the papain superfamily, including cathepsins B, C, H, and L. Cystatins form 1:1 reversible complexes with CPs, in competition with the substrate, but in some cases the binding is so tight as to be physiologically irreversible. (2) THE CYSTATIN SUPERFAMILYExamination of mammalian tissues and serum revealed several CP inhibitors ranging in si...

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Cystatin M/E Expression is Restricted to Differentiated Epidermal Keratinocytes and Sweat Glands: a New Skin-Specific Proteinase Inhibitor that is a Target for Cross-Linking by Transglutaminase

Cited by 96 publications

References 61 publications

Epigenetic Silencing of the Tumor Suppressor Cystatin M Occurs during Breast Cancer Progression

Epigenetic Silencing of the Tumor Suppressor Cystatin M Occurs during Breast Cancer Progression

Cystatin M suppresses the malignant phenotype of human MDA-MB-435S cells

Salivary (SD-Type) Cystatins: Over One Billion Years in the Making—But to What Purpose?

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