PMC:3583298 / 24630-26499 JSONTXT

{"project":"2_test","denotations":[{"id":"21874045-19952108-79138709","span":{"begin":455,"end":459},"obj":"19952108"},{"id":"21874045-19952108-79138709","span":{"begin":455,"end":459},"obj":"19952108"},{"id":"21874045-11399427-79138710","span":{"begin":1113,"end":1117},"obj":"11399427"},{"id":"21874045-11399427-79138710","span":{"begin":1113,"end":1117},"obj":"11399427"},{"id":"21874045-12114024-79138711","span":{"begin":1138,"end":1142},"obj":"12114024"},{"id":"21874045-12114024-79138711","span":{"begin":1138,"end":1142},"obj":"12114024"},{"id":"21874045-18842113-79138712","span":{"begin":1152,"end":1156},"obj":"18842113"},{"id":"21874045-18842113-79138712","span":{"begin":1152,"end":1156},"obj":"18842113"},{"id":"21874045-9005851-79138713","span":{"begin":1211,"end":1215},"obj":"9005851"},{"id":"21874045-9005851-79138713","span":{"begin":1211,"end":1215},"obj":"9005851"},{"id":"21874045-11807556-79138714","span":{"begin":1324,"end":1328},"obj":"11807556"},{"id":"21874045-11807556-79138714","span":{"begin":1324,"end":1328},"obj":"11807556"},{"id":"21874045-18974121-79138715","span":{"begin":1584,"end":1588},"obj":"18974121"},{"id":"21874045-18974121-79138715","span":{"begin":1584,"end":1588},"obj":"18974121"},{"id":"21874045-10884376-79138716","span":{"begin":1601,"end":1605},"obj":"10884376"},{"id":"21874045-10884376-79138716","span":{"begin":1601,"end":1605},"obj":"10884376"},{"id":"21874045-15195141-79138717","span":{"begin":1691,"end":1695},"obj":"15195141"},{"id":"21874045-15195141-79138717","span":{"begin":1691,"end":1695},"obj":"15195141"},{"id":"21874045-15793295-79138718","span":{"begin":1863,"end":1867},"obj":"15793295"},{"id":"21874045-15793295-79138718","span":{"begin":1863,"end":1867},"obj":"15793295"}],"text":"Amplification of the YAP gene locus as well as YAP protein over-expression has been reported in a wide spectrum of human and murine tumors. We have previously shown that YAP is a downstream target of mitogenic Sonic hedgehog signaling that promotes proliferation and inhibits apoptosis of cerebellar granule cell precursors and we showed that YAP is over-expressed and amplified in the Sonic hedgehog-associated class of medulloblastomas (Fernandez et al 2009). Here, we report a new role for YAP in promoting IGF2/Akt-dependent radio-resistance and ongoing proliferation in the presence of unrepaired DNA, illustrating a novel link between Shh signaling, YAP, and the Akt pathway. We show that YAP activity markedly induces IGF2 transcription, in the absence and presence of radiation. IGF2, in turn, activates Akt downstream of PI-3 kinase, providing cells with a survival and proliferative advantage, and allowing them to inactivate cell cycle checkpoints (Figure 7). Many studies have implicated PI-3 kinase and Akt in cell survival, through its effects on FKHR proteins and Bcl2 family members (Brunet et al 2001, Burgering and Kops 2002, Duronio 2008), and Akt is essential for CGNP survival (Dudek et al 1997). Transcriptional profiling of human medulloblastomas has shown increased expression of IGF2 (Pomeroy et al 2002), and our report clearly links high levels of IGF2 expression with the Sonic hedgehog-associated subclass of medulloblastomas. IGF2 has been shown to be indispensable for the formation and progression of Shh-driven murine medulloblastomas (Corcoran et al 2008, Hahn et al 2000) and to synergize with Sonic Hedgehog in the induction of tumor formation (Rao et al 2004). IGF2 has previously been shown to promote proliferation of medulloblastoma cells and cerebellar neural cell precursors through the activation of Akt (Hartmann et al 2005)."}