UC San Diego

Caspase-2 RNA exists as two, distinct species: Caspase-2L, which is ubiquitously expressed throughout the body, and Caspase-2S, whose expression only reaches detectable levels in the brain. There has been significant research that describes how Caspase-2S levels are regulated by the cellular components that regulate alternative splicing. There is, however, a paucity of data that explores how Caspase-2S levels are regulated by RNA disposal mechanisms such as Nonsense-Mediated Decay (NMD) and, to date, there is no published evidence concerning the brain and Caspase- 2S. The initial data-containing chapter of this work is comprised of data from experiments in which the cellular NMD machinery was inhibited by chemicals or by shRNA- mediated knowckdown. The resulting data from these experiments strongly indicate that Caspase-2S is a target of NMD. The ensuing chapter contains data derived from the P19 neuronal cell culture system as well as in vivo mouse experiments and attempts to address the question of whether the elevated Caspase-2S levels in the brain are due to abrogated NMD. The final chapter of data addresses the question of whether the chemical Etoposide/VP16, a well-established inducer of Caspase-2S, upregulates Caspase-2S by targeting and inhibiting the cellular NMD system