Program Director: Dan Spandau, PhD
Eukaryotic cells have evolved a myriad of mechanisms to protect themselves from environmental stressors such as UVB light. One such mechanism is the translational control of proteins, which allows stressed cells to conserve resources and rapidly reconfigure gene expression to enhance cell repair. A central mechanism directing translational control involves phosphorylation of the subunit of eukaryotic initiation factor 2 (eIF2~P). eIF2~P represses general translation initiation through a reduced ability of eIF2 to combine with GTP and transport the initiator Met-tRNAiMet to ribosomes for the initiation mRNA translation. Mammalian eIF2 can be phosphorylated by one of four eIF2 kinases, each of which is activated by distinct stress conditions, including UVB irradiation. The convergence of diverse stressors onto this one phosphorylation event has led to this stress response pathway being referred to as the Integrated Stress Response (ISR). This lab team has demonstrated one of these kinases, GCN2, is critically important for keratinocytes to survive exposures to UVB. Interestingly, GCN2 is also essential for normal differentiation of the epidermis. Investigators here hypothesize that abrogation of GCN2 signaling in the skin contributes to the development of a wide range of skin diseases and could provide an intervention point for future therapies.
The ISR is a mechanism by which cells response to a variety of stressors via the conservation of enAn emerging area of interest in my laboratory is how the regulation of protein translation affects the manner in which human keratinocytes respond to UVB irradiation. Thus far, this lab has demonstrated that UVB causes a global inhibition of protein synthesis and a corresponding increase in the translation of proteins necessary to manage the cellular consequences of UVB-induced damage.
Research in the laboratory centers on defining how keratinocytes in the epidermis respond to environmental stress, primarily the ultraviolet components of sunlight. The consequences of the failure to appropriately react to these stresses often lead to skin disease and neoplasia. Studies from this team have focused on two specific response pathways: the insulin-like growth factor signaling pathway and the integrated stress response.