KERATINOCYTE DIFFERENTIATION IN HUMAN DISEASE
Previous and current research
The main interest of my laboratory is studying the
cell and molecular biology of non-melanoma skin cancer. This
includes the study of the cells, which make up the bulk of
the epidermis, the epidermal keratinocytes. We have studied
for many years the terminal differentiation pathway of epidermal
keratinocytes, particularly the major cytoskeletal proteins:
keratins. We have developed reagents to study changes in keratin
gene expression in keratinocytes cultured in complex organotypical
models and following transplantation. Keratins 15 and 19 are
expressed in sub-sets of keratinocyte populations in the basal
compartment of the epidermis, and their relationship with
epidermal stem cells is being explored in relation to proliferative
potential, and in comparison with other markers of epidermal
progenitor cells. We have identified changes that occur in
the development of tumours and recently point mutations in
keratins and keratin-associated proteins in skin diseases.
Candidate genes have also been identified for some familial
cancer syndromes with cutaneous manifestations such as the
tylosis and oesophageal cancer gene (Howell Evans syndrome).
Work on intermediate filament associated proteins has also
led to the identification of mutations in plectin in muscular
dystrophy and connexins in hereditary sensorineural deafness.
Connexins form a large multigene family, which assemble as
components of gap junctions called connexons, which are critical
for cell communication. The identification of different connexins
in basal and suprabasal epidermal compartments has led to
cloning of further cutaneous connexins and an appreciation
that there are significant changes in connexins in skin carcinogenesis.
The role of connexins in the regulation of keratinocyte differentiation
is being further explored.
The clinical skin cancer centre attached to the ICRF Skin
Tumour Laboratory has special expertise in the management
of non-melanoma skin cancer in transplant recipients and in
the study of familial cancer syndromes, which give us insight
into new candidate genes involved in molecular carcinogenesis.
Further studies of clinical trials of new antiviral and chemopreventive
agents are being initiated in these patients.
Future projects
We intend to continue working on the role of keratin filament
assembly and keratin interactions with the junctional complex
of the cell membrane, including desmosomes, hemidesmosomes
and the cornified envelope to understand the pathway of epidermal
differentiation. We wish to progress to understanding gene
regulation of these proteins. We are identifying markers of
epidermal stem cells and studying the role of p16 and telomerase
in immortalisation of keratinocytes.
