Abstract
Abstract Tumor progression locus-2 (Tpl-2) kinase is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family that has been implicated in cellular transformation. The enhanced expression of this protein has been shown to activate both the MAPK and c-Jun N-terminal kinase (JNK) pathways. However the molecular mechanisms responsible for the oncogenic potential of Tpl-2 are still largely unknown. Here, we show that Tpl-2 interacts with p53 both in vitro and ex vivo. The overexpression of Tpl-2 inhibits the phosphorylation of p53 at serine 15 induced by EGF by upregulating the activity of protein phosphatase 2A (PP2A). In addition, the EGF-induced p53 activity was suppressed in the Tpl-2-wild-type-transfeted HEK 293 cells, but had no effect in the Tpl-2-mutant (S413A)-transfected cells. Furthermore, the Tpl-2 wild type, but not Tpl-2 mutant (S413A), showed increased EGF-induced c-fos promoter activity, followed by AP-1 transactivation activity, which is associated with the cell transformation prompted by the H-Ras-Tpl-2-AP-1 signaling axis. These results suggest that Tpl-2 plays an important role in EGF-induced carcinogenesis by inactivating the p53 tumor suppressor. Citation Information: Cancer Res 2009;69(23 Suppl):A46.
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