Abstract 15: Phosphorylation defective mutant Bcl-xL knockin mice exhibit behavioral abnormalities linked with neurodevelopmental disorders

Bcl-xL, a close homolog of Bcl2, is an important regulator of apoptosis and is overexpressed in many human cancers including neuroblastoma. Previously we have discovered that the regulation of phosphorylation of Bcl-xL on serine 62 residue by tubulin-binding anticancer drugs at mitosis may function as a checkpoint to permit apoptosis of cancer cells. However, the physiological significance of Bcl-xL phosphorylation still remains obscure. With a view to comprehending the functional relevance of Bcl-xL phosphorylation in vivo, we have generated knock-in mice expressing an unphosphorylable ser62 (equivalent to human ser62), by substitution with an alanine residue. Thus placing the phosphorylation-defective mutant of Bcl-xL into the germ line of mice creates opportunities to observe the effects of endogenous phosphorylation in the context of multicellular organisms. Since Bcl-xL has been shown to be maintained at high level in CNS, initially a full behavioral phenotyping battery was carried out with wild type (WT) and Bcl-xLS62A(+/+) mice. Born at Mendelian ratios, the Bcl-xLS62A(+/+) mice demonstrated reduced startle response and reduced PPI (Prepulse inhibition) at lower PPI amplitudes compared to WT mice. Moreover, cognitive deficits were noted in the passive avoidance task between Bcl-xLS62A(+/+) mice and WT littermates. These data indicate that mutation in the phosphorylation site of Bcl-xL drive a range of functional abnormalities and many of the observed behavioral abnormalities in Bcl-xLS62A(+/+) mice are consistent with neurodevelopmental disorders. In all, our findings suggest that endogenous phosphorylation of antiapoptotic protein Bcl-xL might play a critical role in neurodevelopment and subsequent CNS functional output. Further molecular analysis on the effect of blocking of endogenous phosphorylation of Bcl-xL on neuronal apoptosis will be discussed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 15. doi:10.1158/1538-7445.AM2011-15