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Carcinogenesis Advance Access originally published online on February 12, 2009
Carcinogenesis 2009 30(4):682-689; doi:10.1093/carcin/bgp040
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF

Prem Khanal, Kwang-Youl Lee1, Keon-Wook Kang, Bong Seok Kang2 and Hong Seok Choi*

College of Pharmacy, Chosun University, Seosuk-dong, Dong-gu, Gwangju 501-759, South Korea
1 College of Pharmacy, Chonnam National University, Yongbong-dong, Buk-gu, Gwangju 500-757, South Korea
2 Bio-Medical Research Institute, Kyungpook National University Hospital, Daegu 700-721, South Korea

* To whom correspondence should be addressed. Tel: +82 62 230 6379; Fax: +507 437 9606; Email: chs{at}chosun.ac.kr

Tumor progression locus-2 (Tpl-2) kinase is a member of the mitogen-activated protein kinase kinase kinase family that has been implicated in cellular transformation. The enhanced expression of this protein has been shown to activate both the mitogen-activated protein kinase and c-Jun N-terminal kinase pathways. However, the molecular mechanisms responsible for the oncogenic potential of Tpl-2 are still largely unknown. Here, we showed that Tpl-2 interacted with p53 both in vitro and ex vivo. The overexpression of Tpl-2 inhibited the epidermal growth factor (EGF)-induced p53 phosphorylation (Ser15) through upregulating the activity of protein phosphatase 2A, which interacted with p53 stimulated by EGF. Also, the EGF-induced p53 activity was suppressed in the Tpl-2 wild-type (WT)-transfected HEK 293 cells, but had no effect in the Tpl-2-mutant (S413A)-transfected cells. Furthermore, introduction of small interfering RNA-Tpl-2 into HEK 293 cells resulted in decreased cell viability compared with only adenovirus-p53-infected cells. In addition, the Tpl-2 WT, but not Tpl-2 mutant (S413A), showed increased EGF-induced c-fos promoter activity, followed by activator protein 1 (AP-1) transactivation activity, which was associated with the cell transformation prompted by the H-Ras-Tpl-2-AP-1 signaling axis. These results indicated that the Ser413 of Tpl-2 plays an important role in EGF-induced carcinogenesis as well as inactivation of the p53.

Abbreviations: AP-1, activator protein 1; DD, DNA-binding domain; DMEM, Dulbecco's modified Eagle's medium; EGF, epidermal growth factor; ERK, extracellular signal-regulated kinase; FBS, fetal bovine serum; GFP, green fluorescent protein; HA, hemagglutinin; HRP, horseradish peroxidase; IP, immunoprecipitation; PP2A, protein phosphatase 2A; siRNA, small interfering RNA; TAD, transcriptional activation domain; TET, tetramerization domain; Tpl-2, tumor progression locus-2; WT, wild-type

Received September 1, 2008; revised December 24, 2008; accepted February 6, 2009.


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