Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Physiology

Supervisor

Dr. Lina Dagnino

Abstract

Integrin-linked kinase (ILK) is a ubiquitous scaffold protein that mediates cellular responses to integrin stimulation by extracellular matrix proteins. Mice with inactivation of the Ilk gene in squamous epithelia display defects in skin regeneration after injury, failure to thrive, and perinatal death. ILK-deficient epidermis exhibits reduced adhesion to the basement membrane and impaired hair follicle morphogenesis. In culture, ILK-deficient keratinocytes fail to attach and spread efficiently, and demonstrate decreased survival. We now show that ILK-deficient keratinocytes exhibit lower proliferative capacity and increased apoptosis in the absence or presence of growth factors. This reduced viability appears to be independent of the AKT pathway, as ILK-deficient cells exhibit normal levels of active, phosphorylated AKT. They do, however, display higher levels of cleaved Caspase-3 and PARP, both associated with caspase-dependent programmed cell death. We have also observed an increase in γH2A.X, a marker of DNA double-strand breaks, which is also associated with increased levels of reactive oxygen species (ROS) in these cells. Thus, increased susceptibility to DNA damage due an increase in ROS may lead to decreased cell survival. Our findings underline a distinct, novel role for ILK in promoting keratinocyte survival and a normal redox state.

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