Loss of E-cadherin-mediated cell-cell contacts activates a novel mechanism for up-regulation of the proto-oncogene c-Jun.
Loss of E-cadherin-mediated cell-cell contacts can elicit a signaling pathway that leads to acquisition of an invasive phenotype. Here, we show that at the receiving end of this pathway is the proto-oncogene c-Jun, a member of the activator protein-1 family of transcription factors that play a key role in stimulation of cell proliferation and tumor promotion. Cell separation or abrogation of E-cadherin-mediated cell-cell contacts both cause a dramatic increase in accumulation of the c-Jun protein. Unlike growth factors that enhance the expression of c-Jun by activating the transcription of the c-jun gene, the cell contact-dependent increase in c-Jun accumulation is not accompanied by a corresponding increase in c-Jun mRNA or c-Jun protein stability but rather in the translatability of the c-Jun transcript. Consistently, the increase in c-Jun accumulation is not dependent on activation of the mitogen-activated protein kinase or beta-catenin pathways but is mediated by signals triggered by the restructured cytoskeleton. Depolymerization of the cytoskeleton can mimic the effect of cell separation and cause a dramatic increase in c-Jun accumulation, whereas Taxol inhibits the cell contact-dependent increase. This novel mechanism of c-Jun regulation seems to underlie the robust overexpression of c-Jun in tumor cells of patients with colon carcinoma.
Knirsh
Revital
R
Department of Biochemistry, George S. Wise Faculty of Life Sciences, Tel Aviv University, 69978 Tel Aviv, Israel.
Ben-Dror
Iris
I
Spangler
Barbara
B
Matthews
Gideon D
GD
Kuphal
Silke
S
Bosserhoff
Anja K
AK
Vardimon
Lily
L
D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002450:Cell Communication; D002460:Cell Line; D002645:Chickens; D003599:Cytoskeleton / Q000378:metabolism; D006801:Humans; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D014176:Protein Biosynthesis; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics*
D015820:Cadherins; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D020928:Mitogen-Activated Protein Kinases