|dc.description.abstract||Organ‐transplant recipients (OTRs) on a new class of immunosuppressants,
rapamycin and its analogues, have reduced cutaneous Squamous Cell Carcinomas
(cSCCs). Rapamycin, an mTORC1 inhibitor, is also a known autophagy inducer in
experimental models. Autophagy, which literally means self‐eating, is a cell survival
mechanism but can also lead to cell death. Therefore, the main hypothesis behind
this work is that rapamycin prevents epidermal tumourigenesis by either affecting
epidermal mTOR regulation of autophagy and/or selectively affecting epidermal
AKT isoform activity.
Epidermal keratinocytes move from the proliferating basal layer upwards to the
granular layers where they terminally differentiate, forming a layer of flattened,
anucleate cells or squames of the cornified layer which provides an essential
environmental barrier. However, epidermal terminal differentiation, a specialised
form of cell death involving organelle degradation, is poorly understood.
The work presented in this thesis shows that analysis of the autophagy marker
expression profile during foetal epidermal development, indicates autophagy is
constitutively active in the terminally differentiating granular layer of epidermis.
Therefore, I hypothesize that autophagy is a mechanism of organelle degradation
during terminal differentiation of granular layer keratinocytes.
In monolayer keratinocytes, activation of terminal differentiation is accompanied by
autophagic degradation of nuclear material, nucleophagy. This suggests that
constitutive autophagy is a pro‐death mechanism required for terminal
differentiation. In cultured keratinocytes and in epidermal cultures, rapamycinmediated
mTORC1 inhibition strongly increases AKT1 activity as well as up‐regulates
constitutive granular layer autophagy promoting terminal differentiation.
Therefore, autophagy is an important fundamental process in keratinocytes which
may be the mechanism by which terminally differentiating keratinocytes of the epidermal granular layer degrade their organelles required for barrier formation.
This may have implications for the treatment of patients with barrier defects like
psoriasis. In immunosuppressed OTRs, rapamycin may promote epidermal
autophagy and AKT1 activity adding to its anti‐tumourigenic properties.||en_US