However, little is known regarding whether TIG3 regulates skin cancer cell survival and tumor progression. We show that expression of TIG3 causes a marked reduction in SCC-13 cell number that is associated with reduced G1 and S phase events and increased sub-G1 DNA content. These cell cycle changes are associated with TIG3-dependent changes in cell cycle regulatory protein level. TIG3 expression reduces cyclin D1 and cyclin E levels and increases the level of the p21 cyclin-dependent kinase inhibitor. These findings are consistent with a reduction in cell progression through the G1/S transition. In addition, we demonstrate that TIG3 increases SCC-13 cell apoptosis as evidenced by increased production of activated caspase 9 and 3 and increased cleaved PARP. Moreover, immunostaining studies reveal cleaved PARP accumulates in TIG3-positive cells. These results are particularly interesting as TIG3 does not cause apoptosis in U0126 MEK inhibitor normal human keratinocytes. Instead, TIG3 causes the cells to undergo differentiation. In contrast, mutant forms of TIG3 cause apoptosis in normal human keratinocytes. The fact that TIG3 causes apoptosis in cancer cells suggests a different mechanism of action in normal versus transformed cells. In addition, some of these changes are associated with changes in target gene mRNA level. For example, the TIG3-dependent increase in p21 protein is associated with a parallel increase in p21 encoding mRNA, indicating that TIG3 regulates p21 gene transcription or RNA stability. We do not presently know whether this action is direct or indirect. Ischemia contributes to multiple ocular diseases, including glaucoma and diabetic retinopathy. Acute retinal ischemia caused by high ocular pressure followed by reperfusion leads to neuronal and vascular degeneration, and to inflammatory changes, including up-regulation of TNF-a, COX-2 and iNOS. All of these abnormalities have also been found to be elevated in rodent models of diabetic retinopathy, but the changes in retinal I/R injury develop more rapidly and severely. Investigators have used the rodent retinal I/R model to study the mechanisms involved in the neurovascular degeneration and to seek therapeutic ways to prevent this degeneration. The mechanisms triggering retinal neurovascular degeneration are not fully understood. Several pathways have been demonstrated to play important roles in neuronal degeneration after I/R injury, including glutamate excitotoxicity, oxidative and nitrative stress, and inflammation.