Disabled-2 Exerts Its Tumor Suppressor Activity by Uncoupling c-Fos Expression and MAP Kinase Activation
Journal of Biological Chemistry
Disabled-2 (Dab2) is a putative tumor suppressor in breast and ovarian cancers. Its expression is lost in a majority of tumors, and homozygous deletions have been identified in a small percentage of tumors. Dab2 expression is absent or very low in the majority of breast and ovarian cancer cell lines, including MCF-7 and SK-Br-3 breast cancer cells. Transfection and expression of Dab2 in MCF-7 and SK-Br-3 cells suppress tumorigenicity. The cells reach a much lower saturation density and have
... ensity and have reduced ability to form colonies on agar plates. In examining the signal transduction pathway of Dab2transfected cells, we found that serum-stimulated c-Fos expression was greatly suppressed; however, the effects of Dab2 on MAPK family kinases were not as consistent. In MCF-7 and SK-Br-3 cells, although c-Fos expression was suppressed, the Erk1/2, JNK, and p38 MAPK activities were unchanged or even increased. Serum-stimulated c-Fos expression is dependent on MAPK/Erk activity because the MEK inhibitor PD98059 suppresses Erk activity and c-Fos expression. Therefore, Dab2 appears to uncouple MAPK activation and c-fos transcription. Thus, we conclude that Dab2 re-expression suppresses tumorigenicity by reducing c-Fos expression at a site downstream of the activation of MAPK family kinases. Because Dab2 is frequently lost in cancer, the uncoupling of MAPK activation and c-Fos expression may be a favored target for inactivation in tumorigenicity.