Abstract #2198: p27 (Kip1) gene dosage plays a role in cell cycle progression and tumor suppression in Shh-mediated medulloblastoma

Medulloblastoma, a brain tumor arising in the cerebellum, is the most common solid childhood malignancy. Gaining insight into mechanisms regulating transformation of medulloblastoma cells-of-origin will lead to development of better treatments and new mouse models in which to test those treatments. Cerebellar granule neuron precursors (CGNPs) are proposed cells-of-origin for certain classes of medulloblastoma. These cells require signaling by the secreted factor Sonic hedgehog (Shh) for their proliferation during brain development. Mutations causing aberrant activation of the Shh signaling pathway are implicated in human and mouse medulloblastomas. To promote proliferation and oncogenic transformation, Shh alone is not sufficient; cooperative interactions with other signaling pathways are required. We previously showed that loss or inactivation of the tumor suppressor Tuberous Sclerosis Complex (TSC), composed of the proteins TSC1 and TSC2, leads to cyclin dependent kinase inhibitor p27 (Kip1) loss or mislocalization in CGNPs and in Shh-mediated medulloblastoma. Using mice that express an activated mutant allele of the Shh receptor component Smoothened (SmoA1), we find that SmoA1 mice with p27 heterozygosity have a decreased survival compared to mice having two wild-type p27 alleles. Also, these mice maintain wild-type p27 protein, which is aberrantly localized to the cytoplasm. Interestingly, SmoA1 mice with complete loss of p27 do not show enhanced medulloblastoma incidence, resembling instead tumor latency of SmoA1 +/+ p27 +/+ mice. This may reflect the requirement for p27 in recruiting cyclin D/cdk4/6 to promote cell cycle progression. Together, our data indicate that the dosage of p27 plays a role in cell cycle progression and tumor suppression in Shh-mediated medulloblastoma expansion. We are currently investigating how proteins interacting with p27 play roles in cell cycle progression/regulation in medulloblastoma. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2198.