Wound Healing, UV damage and the Stress Response

Wound Healing, GCN2 and the Stress Response

The Integrated Stress Response is associated with cellular management of environmental stress. Contributors to chronic wounds such as diabetes and poor nutrition are potential triggers of the Integrated Stress Response. The role of GCN2 in both wound healing and the ISR indicate that this may be a critical target for advancing enhanced therapies for chronic wounds.

Wound Healing is a naturally occurring biological process as a reaction to tissue injury. The healing process occurs in mutiple phases, culminating in remodeling of wounded tissues. In healthy individuals, wound healing usually occurs without complications, however, in diabetes and with aging, wound healing can become impaired, leading to chronic wounds. The focus of our research is to delineate the cascade of events that lead to proper wound healing and the role eIF2 kinase GCN2 and translational control play in collective cell migration during wound repair. We discovered that GCN2 facilitates wound repair in different human and mouse skin models and we are delineating the underlying mechanisms and therapeutic utility of GCN2-directed repair processes.

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 (Indiana University School of Medicine, Department of Dermatology)

Keratinocyte differentiation is affected by the lack of GCN2

References:

Miles RR, Amin PH, Diaz MB, Misra J, Aukeman E, Das A , Ghosh N, Guith T, Knierman MD, Roy S, Spandau DF, Wek RC (2021)

The eIF2 kinase GCN2 directs keratinocyte collective cell migration during wound healing via coordination of reactive oxygen species and amino acids.

J Biol Chem Nov;297(5):101257

Colliert AE, Spandau DF, Wek RC (2018)

Translational control of a human CDKN1A mRNA splice variant regulates the fate of UVB-irradiated human keratinocytes. Mol Biol Cell. Jan:29(1):29-41

Collier AE, Wek RC, Spandau DF (2017)

Human Keratinocyte Differentiation Requires Translational Control by the eIF2α Kinase GCN2.

J Invest Dermatol. Sep;137(9):1924-1934.

Collier AE, Wek RC, Spandau DF (2015)

Translational Repression Protects Human Keratinocytes from UVB-Induced Apoptosis through a Discordant eIF2 Kinase Stress Response.

J Invest Dermatol. Oct;135(10):2502-11.