The Role Of P38/Mapk14 In Sonic Hedgehog-Driven Cgnp Proliferation

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Development of the cerbellum occurs primarily postnatally and is marked by a rapid proliferation of cerebellar granule neuron precursors (CGNPs). This proliferation requires the activity of the mitogen Sonic Hedgehog (Shh). The rapid proliferation stage of CGNPs has led to speculation that they are the cells of origin for some classes of medulloblastoma, the most common solid pediatric tumor. Since MAP kinases play important roles in many aspects of development, proliferation, and cancer we investigated if any of the three major classes of MAP kinases were involved in Shh-driven CGNP proliferation. We have previously shown that p42/p44 ERK MAP kinases are not involved in Shh signaling in CGNP proliferation. We have also shown that JNK/SAP kinases are not involved in Shh-driven proliferation. However, p38/MAPK14 is induced and activated in proliferating CGNPs compared to CGNPs that exit the cell cycle and differentiate in the absence of Shh. Other known pathway components upstream and downstream of MAPK14, such as ASK1, MKK3 and ATF-2, are also activated in the presence of Shh. Antioxidants such as lipoic acid and n-acetyl-cysteine that relieve oxidative stress reduced Shh-induced activation of MAPK14 and caused a marked decrease in CGNP proliferation measured by Ki67 and BrdU staining. We are currently investigating the role of oxidative stress and MAPK14 in CGNP proliferation by over-expressing and knocking down MAPK14 in CGNPs under oxidative stress conditions. Preliminary data suggests that knocking down MAPK14 reduces CGNP proliferation. Elucidating the role of MAPK14 pathway in CGNP proliferation will not only help us understand normal cerebellum development but may also lead to possible therapies for diseases where constitutive Shh signaling has been shown to play a role such as some classes of medulloblastoma and Gorlin's syndrome. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-13.