c-Jun N-terminal kinase mediates AML1-ETO protein-induced connexin-43 expression.
AML1-ETO fusion protein, a product of leukemia-related chromosomal translocation t(8;21), was reported to upregulate expression of connexin-43 (Cx43), a member of gap junction-constituted connexin family. However, its mechanism(s) remains unclear. By bioinformatic analysis, here we showed that there are two putative AML1-binding consensus sequences followed by two activated protein (AP)1 sites in the 5'-flanking region upstream to Cx43 gene. AML1-ETO could directly bind to these two AML1-binding sites in electrophoretic mobility shift assay, but luciferase reporter assay revealed that the AML1 binding sites were not indispensable for Cx43 induction by AML1-ETO protein. Conversely, AP1 sites exerted an important role in this event. In agreement, AML1-ETO overexpression in leukemic U937 cells activated c-Jun N-terminal kinase (JNK), while its specific inhibitor SP600125 effectively abrogated AML1-ETO-induced Cx43 expression, indicating that JNK signaling pathway contributes to AML1-ETO induced Cx43 expression. These results would shed new insights for understanding mechanisms of AML1-ETO-associated leukemogenesis.
Gao
Feng-Hou
FH
Department of Pathophysiology, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai 200025, China.
Wang
Qiong
Q
Wu
Ying-Li
YL
Li
Xi
X
Zhao
Ke-Wen
KW
Chen
Guo-Qiang
GQ
D000873:Anthracenes / Q000494:pharmacology; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism / Q000502:physiology*; D007938:Leukemia / Q000473:pathology; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors / Q000502:physiology*; D014407:Tumor Cells, Cultured
D000873:Anthracenes; D018031:Connexin 43; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D000075142:RUNX1 Translocation Partner 1 Protein; C082222:RUNX1T1 protein, human; D014157:Transcription Factors; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases