Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway.

Gadd45a, a p53-regulated and DNA damage-inducible gene, is implicated in protection against tumor malignancy, although the underlying mechanism remains to be defined further. Here we demonstrate that Gadd45a plays an important role in suppression of tumor angiogenesis. Gadd45a deletion significantly increases microvessel density in tumors and stimulates an angiogenic response in a chicken embryo chorioallantoic membrane assay. Disruption of endogenous Gadd45a promotes tube formation and migration of endothelial cells. We further show that Gadd45a deletion increases phosphorylation of at Ser-727 and, in turn, elevates the duanyu18133 transcriptional activity. This process substantially induces both expression and secretion of VEGFa, a duanyu18133 responsive gene, and promotes tumor angiogenesis. Interestingly, Gadd45a is able to physically associate with mammalian target of rapamycin (mTOR), a kinase that mediates Ser-727 phosphorylation of The interaction of Gadd45a with mTOR suppresses duanyu18133 phosphorylation at Ser-727 and leads to down-regulated expression of VEGFa. Further analysis reveals that Gadd45a overexpression attenuates the association between mTOR and whereas Gadd45a disruption strengthens this interaction, indicating that Gadd45a suppression of duanyu18133 phosphorylation is mainly through the dissociation of mTOR with duanyu18133. Taken together, these findings provide the first evidence that Gadd45a inhibits tumor angiogenesis via blocking of the pathway.

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