GONUTS has been updated to MW1.31 Most things seem to be working but be sure to report problems.

Have any questions? Please email us at ecoliwiki@gmail.com

PMID:23329839

From GONUTS
Jump to: navigation, search
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

Significance

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

Notes

See also

References

See Help:References for how to manage references in GONUTS.