UV, Skin and the Stress Response
Translational control in human keratinocyte differentiation and adaptation to stress
UVB is a significant risk factor in the development of non-melanoma skin cancer, which accounts for a large percentage of all cancers diagnosed in the US. Following UVB-induced DNA damage, replicating keratinocytes undergo a cell cycle arrest to facilitate repair of damaged DNA. A central mechanism for cell resistance to UVB stress involves phosphorylation of eukaryotic initiation factor -2 (eIF2-P), which directs global and gene-specific translation. However, the underlying mechanisms by which translational control through eIF2-P affords keratinocytes resistance to UVB is largely unknown. We are pursuing genome-wide analyses using RNA-Seq and ribosomal profiling to discern the key downstream effector of eIF2-P signaling that provide UVB resistance of eIF2-P. Additionally, we have determined that eIF2-P is a central player in the progression of keratinocyte differentiation. This line of investigation will provide insight into the mechanisms underlying the initiation and progression of non-melanoma skin cancers and the processes by which altered skin differentiation can contribute to psoriasis and related disorders. This research is being carried out in collaboration with Dr. Dan Spandau from the Department of Dermatology.
Nuclei are stained with DAPI, eIF2 in red
Keratinocyte differentiation is affected by the lack of GCN2
Collier AE, Wek RC, Spandau DF Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response. J Invest Dermatol. 2015 Oct;135(10):2502-11.