Role of PKCepsilon in cell division and differentiation: implication for genomic instability and autoimmunity

Protein kinase C epsilon is a serine/threonine kinase involved in many cellular functions, including cell growth, proliferation and differentiation. Due to its unique protective role in ischemic preconditioning, along with its oncogenic potential, PKCepsilon is considered one of the most interesting isoform among the PKCs. During my PhD, I investigated the involvement of PKCepsilon in two independent but correlated biological processes: cell division and cell differentiation. Cell division is an extremely regulated process which involves the duplication of the genome of a cell and its segregation into two identical daughter cells. Accurate chromosome segregation during cell division is achieved through the assembly of a bipolar mitotic spindle. It has been demonstrated that PKCepsilon is involved in several cell cycle processes, such as cytokinesis and mitotic catenation resolution during metaphase-anaphase transition. However, a PKCepsilon engagement in earlier (pre)mitotic events was unknown. Here, I describe a novel cell cycle role for PKCepsilon in coordinating centrosome migration and mitotic spindle assembly by regulating cytoplasmic dynein function. Interestingly, PKCepsilon dependency of mitotic spindle organization is related to the properties of transformed cells, supporting PKCepsilon as a potential cancer therapeutic target. PKCepsilon is also implicated in proliferation of CD4+ T lymphocytes by regulating cell sensitivity to TGF1beta, well-known to inhibit proliferation. Particularly, PKCepsilon has been found overexpressed in CD4+ cells from patients with Hashimoto Thyroiditis, an autoimmune disease characterized by abnormal lymphocyte proliferation and activation, suggesting an implication for PKCepsilon in immune-mediated diseases. A novel subset of Interleukin-17 (IL-17) producing CD4+ T cells (Th17) has been recently shown to promote inflammatory responses and to contribute to the pathogenesis of autoimmune diseases such as psoriasis. Mechanisms that underlie human in vitro Th17 differentiation are still unclear. However, it has been demonstrated that Stat3 signalling pathway is essential for Th17 differentiation. In this study, I demonstrate that PKCepsilon is overexpressed in circulating CD4+ T cells from patients with psoriasis and that its expression correlates with the severity of the disease. Furthermore, I show that PKCepsilon is involved in vitro Th17 lymphocytes polarization from CD4+ naïve cells isolated from peripheral blood by regulating STAT3 signalling pathway. Collectively these results, confirming the clinical relevance of PKCepsilon in psoriasis, support the hypothesis that PKCepsilon might be a potential therapeutic target for Th17-mediated disease. Overall, the data obtained during my PhD add knowledge to the pathological implication of Protein Kinase Cepsilon both in cell division and cell differentiation.