Modulation of cellular migration and survival by c-Myc through the downregulation of urokinase (uPA) and uPA receptor.
It has been proposed that c-Myc proapoptotic activity accounts for most of its restraint of tumor formation. We established a telomerase-immortalized human epithelial cell line expressing an activatable c-Myc protein. We found that c-Myc activation induces, in addition to increased sensitivity to apoptosis, reductions in cell motility and invasiveness. Transcriptome analysis revealed that urokinase (uPA) and uPA receptor (uPAR) were strongly downregulated by c-Myc. Evidence is provided that the repression of uPA and uPAR may account for most of the antimigratory and proapoptotic activities of c-Myc. c-Myc is known to cooperate with Ras in cellular transformation. We therefore investigated if this cooperation could converge in the control of uPA/uPAR expression. We found that Ras is able to block the effects of c-Myc activation on apoptosis and cellular motility but not on cell invasiveness. Accordingly, the activation of c-Myc in the context of Ras expression had only minor influence on uPAR expression but still had a profound repressive effect on uPA expression. Thus, the differential regulation of uPA and uPAR by c-Myc and Ras correlates with the effects of these two oncoproteins on cell motility, invasiveness, and survival. In conclusion, we have discovered a novel link between c-Myc and uPA/uPAR. We propose that reductions of cell motility and invasiveness could contribute to the inhibition of tumorigenesis by c-Myc and that the regulation of uPA and uPAR expression may be a component of the ability of c-Myc to reduce motility and invasiveness.
Alfano
Daniela
D
Institute of Genetics and Biophysics Adriano Buzzati-Traverso, Consiglio Nazionale delle Ricerche (CNR), Via P. Castellino 111, 80131 Naples, Italy.
Votta
Giuseppina
G
Schulze
Almut
A
Downward
Julian
J
Caputi
Mario
M
Stoppelli
Maria Patrizia
MP
Iaccarino
Ingram
I
D017209:Apoptosis / Q000502:physiology; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D018925:Chemokines / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D020868:Gene Silencing; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D018925:Chemokines; D017077:Culture Media, Conditioned; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051741:Kruppel-Like Transcription Factors; D016271:Proto-Oncogene Proteins c-myc; D055293:Receptors, Urokinase Plasminogen Activator; D016159:Tumor Suppressor Protein p53; C107961:ZBTB17 protein, human; D014568:Urokinase-Type Plasminogen Activator; D018631:ras Proteins