PMID:23329839

Citation	Yang, F, Zhang, W, Li, D and Zhan, Q (2013) Gadd45a suppresses tumor angiogenesis via inhibition of the mTOR/STAT3 protein pathway. J. Biol. Chem. 288:6552-60
Abstract	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 STAT3 at Ser-727 and, in turn, elevates the STAT3 transcriptional activity. This process substantially induces both expression and secretion of VEGFa, a STAT3 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 STAT3. The interaction of Gadd45a with mTOR suppresses STAT3 phosphorylation at Ser-727 and leads to down-regulated expression of VEGFa. Further analysis reveals that Gadd45a overexpression attenuates the association between mTOR and STAT3, whereas Gadd45a disruption strengthens this interaction, indicating that Gadd45a suppression of STAT3 phosphorylation is mainly through the dissociation of mTOR with STAT3. Taken together, these findings provide the first evidence that Gadd45a inhibits tumor angiogenesis via blocking of the mTOR/STAT3 pathway.
Links	PubMed PMC3585088 Online version:10.1074/jbc.M112.418335
Keywords	Animals; Cell Cycle Proteins/genetics; Cell Cycle Proteins/metabolism; Cell Line, Tumor; Chick Embryo; Gene Expression Regulation, Neoplastic/genetics; Mice; Mice, Knockout; Neoplasm Proteins/genetics; Neoplasm Proteins/metabolism; Neoplasms/genetics; Neoplasms/metabolism; Neovascularization, Pathologic/genetics; Neovascularization, Pathologic/metabolism; Neovascularization, Pathologic/pathology; Nuclear Proteins/genetics; Nuclear Proteins/metabolism; Phosphorylation/genetics; STAT3 Transcription Factor/genetics; STAT3 Transcription Factor/metabolism; Signal Transduction; TOR Serine-Threonine Kinases/genetics; TOR Serine-Threonine Kinases/metabolism; Vascular Endothelial Growth Factor A/biosynthesis; Vascular Endothelial Growth Factor A/genetics
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Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:GA45A		GO:0043537: negative regulation of blood vessel endothelial cell migration	ECO:0000315:		P		Figure 3 (d) (in vitro) shows that knockdown of Gadd54a results in blood vessel endothelial cell migration. Therefore, the presence of Gadd54a inhibits this process; it negatively regulates endothelial cell migration.	complete CACAO 12137
HUMAN:GA45A		GO:0000122: negative regulation of transcription from RNA polymerase II promoter	ECO:0000315:		P		Figure 6H shows that absence of Gadd45a results in increased transcriptional activity of STAT3 because of phosphorylation of STAT3 on a Serine residue. Therefore, Gad45a is involved in a process that prevents transcription from an RNA pol II promoter. RNA pol II is the protein that transcribes mRNA in eukaryotes.	complete CACAO 12212
HUMAN:GA45A		GO:1903262: negative regulation of serine phosphorylation of STAT3 protein	ECO:0000315:		P		Figure 6 b and c show that Gadd45a knockdown in human cells (HeLa) results in enhanced transcriptional activity of STAT3 by increasing the STAT3 phosphorylation site on a serine residue.	complete CACAO 12144
HUMAN:GA45A		GO:0071901: negative regulation of protein serine/threonine kinase activity	ECO:0000315:		P		Figure 6B,C shows that Gadd45a is able to prevent the phosphorylation of STAT3 at Ser-727. This means that Gadd45a inhibits the activity of a serine/threonin-specific protein kinase	complete CACAO 12213
MOUSE:GA45A		GO:0016525: negative regulation of angiogenesis	ECO:0000315:		P		Figure 1 shows that Gadd45a deletion promotes angiogenesis and hence tumor growth.	complete CACAO 12134
MOUSE:GA45A		GO:0043537: negative regulation of blood vessel endothelial cell migration	ECO:0000315:		P		Figure 2 (e and f) (in vivo) shows that knockdown of Gadd54a results in blood vessel endothelial cell migration. Therefore, the presence of Gadd54a inhibits this process; it negatively regulates endothelial cell migration	complete CACAO 12138
MOUSE:GA45A		GO:1903262: negative regulation of serine phosphorylation of STAT3 protein	ECO:0000315:		P		Figure 6a and d show that Gadd45a knockdown in mouse cells (MEFs) results in enhanced transcriptional activity of STAT3 by increasing the STAT3 phosphorylation site on a serine residue.	complete CACAO 12143

References

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