Biomedical subjects

M Chidgey

Publications and source records attributed to M Chidgey.

5 recordsLinked to original sources

PubMed2006

Desmocollin switching in colorectal cancer.

The desmocollins are members of the desmosomal cadherin family of cell-cell adhesion molecules. They are essential constituents of desmosomes, intercellular junctions that play a critical role in the maintenance of tissue integrity in epithelia and cardiac muscle. In humans, three desmocollins (Dsc1, Dsc2 and Dsc3) have been described. The desmocollins exhibit tissue-specific patterns of expression; only Dsc2 is expressed in normal colonic epithelium. We have found switching between desmocollins in sporadic colorectal adenocarcinoma with a reduction in Dsc2 protein (in 8/16 samples analysed by immunohistochemistry) being accompanied by de novo expression of Dsc1 (16/16) and Dsc3 (7/16). Similar results were obtained by western blotting of a further 16 samples. No change was found in Dsc2 mRNA, but de novo expression of Dscs 1 and 3 was accompanied by increased message levels. Loss of Dsc2 (8/19) and de novo expression of Dsc1 (11/19) and Dsc3 (6/19) was also found in colorectal adenocarcinomas on a background of colitis. The data raise the possibility that switching of desmocollins could play an important role in the development of colorectal cancer.

Adenocarcinoma↗

PubMed2002

Desmosomes and disease: an update.

Desmosomes play a critical role in the maintenance of normal tissue architecture. Skin blistering can occur when desmosomal adhesion is compromised by antibodies in autoimmune diseases such as pemphigus. Inherited mutations in genes encoding desmosomal constituents can adversely affect the skin, and result in heart abnormalities. Desmosomes may have a tumour suppressor function: expression of desmosomal components is reduced in some human cancers, and desmosomal cadherins have the capacity to suppress the invasiveness of cells in culture. Transgenic animal research has provided important insights into the role of these junctions in normal epithelial morphogenesis and disease.

Animals↗

PubMed2001

Mice lacking desmocollin 1 show epidermal fragility accompanied by barrier defects and abnormal differentiation.

The desmosomal cadherin desmocollin (Dsc)1 is expressed in upper epidermis where strong adhesion is required. To investigate its role in vivo, we have genetically engineered mice with a targeted disruption in the Dsc1 gene. Soon after birth, null mice exhibit flaky skin and a striking punctate epidermal barrier defect. The epidermis is fragile, and acantholysis in the granular layer generates localized lesions, compromising skin barrier function. Neutrophils accumulate in the lesions and further degrade the tissue, causing sloughing (flaking) of lesional epidermis, but rapid wound healing prevents the formation of overt lesions. Null epidermis is hyperproliferative and overexpresses keratins 6 and 16, indicating abnormal differentiation. From 6 wk, null mice develop ulcerating lesions resembling chronic dermatitis. We speculate that ulceration occurs after acantholysis in the fragile epidermis because environmental insults are more stringent and wound healing is less rapid than in neonatal mice. This dermatitis is accompanied by localized hair loss associated with formation of utriculi and dermal cysts, denoting hair follicle degeneration. Possible resemblance of the lesions to human blistering diseases is discussed. These results show that Dsc1 is required for strong adhesion and barrier maintenance in epidermis and contributes to epidermal differentiation.

Aging↗

PubMed1998

Desmosomal adhesion inhibits invasive behavior.

Recent studies of human disease and transgenic animal experiments have clearly demonstrated the importance of desmosomes in normal tissue architecture. Furthermore, desmosomal components are down-regulated in certain types of carcinomas, suggesting a possible role for desmosomes in suppression of invasion and metastasis. However, there is no functional evidence to support such a hypothesis. To obtain such evidence, we needed to generate desmosomal adhesion in an invasive cell line. We show that expression of multiple desmosomal components (the desmosomal cadherins, desmocollin and desmoglein, and the armadillo protein, plakoglobin) in nonadhesive L929 fibroblasts generates adhesion in aggregation assays. This adhesion is specifically blocked by short peptides corresponding to the putative cell adhesion recognition sites of desmocollin and desmoglein. This result provides an experimental demonstration of the functional importance of the cell adhesion recognition sites of desmocollin and desmoglein and indicates that both desmosomal cadherins are specifically involved in this adhesion. Moreover, whereas parental L929 cells are strongly invasive into collagen gels, we show that invasion is substantially inhibited in cells transfected with desmosomal components. Invasion is restored by treating the transfected cells with anti-adhesion peptides, indicating that desmosomal adhesion specifically blocks invasion in culture. Our results support the suggestion that desmosomes have a role in suppression of tumor spreading.

Cadherins↗

PubMed1996

Desmosomes: differentiation, development, dynamics and disease.

Recent evidence on the distribution of desmosomal glycoprotein isoforms that shows their combined expression in individual desmosomes has strengthened the belief that the latter are involved in epithelial differentiation and morphogenesis. It has been shown that cellular interactions and protein kinase C can modulate the adhesive properties of desmosomes in epithelial cell sheets. Genetic studies indicate the involvement of desmosomal components in cancer and epidermal diseases.

Animals↗