In response to a myriad of environmental stresses, including ultraviolet-B (UVB) irradiation, eukaryotic cells rapidly modulate protein synthesis. An important mechanism for translation regulation involves phosphorylation of the a subunit of eukaryotic initiation factor 2 (eIF2a), which results in a rapid decrease in global protein synthesis, concurrent with preferential translation of cytoprotective gene transcripts, via a set of pathways collectively called the Integrated Stress Response (ISR). Although the ISR has been implicated in carcinogenesis in a variety of tissues, little is known about whether the ISR can modulate the development of cancer in human skin. We previously defined the cytoprotective role of the ISR in response to UVB-irradiation of human keratinocytes in vitro, in part through the enhanced translation of genes involved in DNA repair. To address how the ISR is involved during photocarcinogenesis in vivo, we analyzed the expression of ISR proteins (phosphorylated eIF2aeIF2a, ATF4, CHOP, GADD34) in the progression of cutaneous squamous cell carcinoma (cSCC). The tissues examined included normal skin, chronically UVB-exposed skin, actinic keratosis (AK), and cSCC tumors. In normal skin, the expression of ISR proteins was found in the more differentiated layers of the epidermis. In contrast, in chronic UVB-irradiated skin and AK tissue, ATF4 expression was greatly increased in all but the basal cell layer of the epidermis. CHOP and GADD34 expression, as well as eIF2a phosphorylation, followed a similar induced pattern in these tissues. Progression to cSCC resulted in a striking decrease in ISR protein expression. ATF4 and CHOP expression were absent, no eIF2a phosphorylation was detected, and GADD34 expression was greatly diminished. Therefore, the normal ISR response in differentiating keratinocytes is enhanced in AK lesions but silenced as the tumor progresses to cSCC. These results suggest that sustaining the ISR response in UVB-damaged epidermis could be a valuable therapeutic target for the prevention of SCC development. 1141Melanocyte UVB skin damage is inversely affected by S. epidermis versus P. acne Specific skin commensal bacteria, such as Staphylococcus epidermidis (SE), have been implicated in skin cell immune response. Recently, Propionibacterium acnes (PA) has also emerged as an important player in the skin innate immune system, especially with respect to its role in the control of nucleic HDAC 8 and 9 in keratinocytes and monocytes. However, little is known about whether or how the skin microbiome, SE and PA, have effects on conditioning melanocyte behavior after UVB exposure. An in vitro system of UVB irradiated normal human melanocytes (NHM) with 50 mJ/cm 2 was used for this study. NHMs were preconditioned with LTA (lipoteichoic acid, TLR2 ligand), PA and SE supernatant. Irradiated NHM FACS analysis showed that LTA prevented early apoptosis and PA had a strong proapoptotic effect during the early and late apoptotic stage. LTA and SE prevented apoptosis, allowing the proliferatio...

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