PI-3K and Akt are mediators of AP-1 induction by 5-MCDE in mouse epidermal Cl41 cells.
5-Methylchrysene has been found to be a complete carcinogen in laboratory animals. However, the tumor promotion effects of (+/-)-anti-5-methylchrysene-1,2-diol-3,4-epoxide (5-MCDE) remain unclear. In the present work, we found that 5-MCDE induced marked activator protein-1 (AP-1) activation in Cl41 cells. 5-MCDE also induced a marked activation of phosphatidylinositol 3-kinase (PI-3K). Inhibition of PI-3K impaired 5-MCDE-induced AP-1 transactivation, suggesting that PI-3K is an upstream kinase involved in AP-1 activation by 5-MCDE. Furthermore, we found that Akt is a PI-3K downstream mediator for 5-MCDE-induced AP-1 transactivation, whereas another PI-3K downstream kinase, p70(S6K), was not involved in AP-1 activation by 5-MCDE. Moreover, inhibition of Akt activation blocked 5-MCDE-induced activation of extracellular signal-regulated protein kinases (ERKs) and c-Jun NH(2)-terminal kinases (JNKs), whereas it did not affect p38K activation. Consistently, overexpression of a dominant-negative mutant of ERK2 or JNK1 blocked the AP-1 activation by 5-MCDE. These results demonstrate that 5-MCDE is able to induce AP-1 activation, and the AP-1 induction is specifically through a PI-3K/Akt-dependent and p70(S6K)-independent pathway.
Li
Jingxia
J
Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Rd., Tuxedo, NY 10987, USA.
Chen
Haobin
H
Tang
Moon-Shong
MS
Shi
Xianglin
X
Amin
Shantu
S
Desai
Dhimant
D
Costa
Max
M
Huang
Chuanshu
C
D000818:Animals; D002274:Carcinogens, Environmental / Q000494:pharmacology*; D002460:Cell Line; D002911:Chrysenes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000187:drug effects* / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D002274:Carcinogens, Environmental; D002911:Chrysenes; D004791:Enzyme Inhibitors; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D018808:Transcription Factor AP-1; C037783:1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene