PMC:3583298 / 27264-28484 JSONTXT

{"project":"2_test","denotations":[{"id":"21874045-15930307-79138720","span":{"begin":269,"end":273},"obj":"15930307"},{"id":"21874045-15930307-79138720","span":{"begin":269,"end":273},"obj":"15930307"},{"id":"21874045-12391152-79138721","span":{"begin":288,"end":292},"obj":"12391152"},{"id":"21874045-12391152-79138721","span":{"begin":288,"end":292},"obj":"12391152"},{"id":"21874045-12062056-79138722","span":{"begin":311,"end":315},"obj":"12062056"},{"id":"21874045-12062056-79138722","span":{"begin":311,"end":315},"obj":"12062056"},{"id":"21874045-20679434-79138723","span":{"begin":326,"end":330},"obj":"20679434"},{"id":"21874045-20679434-79138723","span":{"begin":326,"end":330},"obj":"20679434"},{"id":"21874045-18955550-79138724","span":{"begin":995,"end":999},"obj":"18955550"},{"id":"21874045-18955550-79138724","span":{"begin":995,"end":999},"obj":"18955550"}],"text":"Defective G2/M checkpoint activation in the presence of DNA damage has been linked to Akt activity. Activation of Akt suppresses the checkpoint by inhibiting the DNA damage response pathways, either ATM/Chk2 or ATR/Chk1, depending on the cellular context (Hirose et al 2005, Kandel et al 2002, Shtivelman et al 2002, Xu et al 2010). In agreement with these studies, we observed a decrease in phosphorylated ATM and Chk2 in irradiated YAP-over-expressing CGNPs and medulloblastoma cells, compared to GFP-expressing cells, and YAP-transduced cells showed fewer DNA damage-induced foci. The effects of YAP on ATM and Chk2 was reversed in the presence of a PI-3 kinase inhibitor, and when we knocked down IGF2, which also abolished the accelerating effect of YAP on DNA damage-dependent focus disassembly. Interestingly, a previous study has shown that aberrant activation of the Shh pathway through Ptc loss-of-function impairs the function of ATR/Chk1, a separate signaling cascade (Leonard et al 2008). We did not detect effects of YAP on this cascade (data not shown); however the impact we report of YAP on ATM/Chk2 may synergize with an already defective DNA damage response due to Smoothened-mediated Chk1 impairment."}