| Autor: |
Weissinger, Eva M., Eissner, Günther, Grammer, Christine, Fackler, Susanne, Haefner, Burkhard, Yoon, Luke S., Lu, Kimberly S., Bazarov, Alex, Sedivy, John M., Mischak, Harald, Kolch, Walter |
| Zdroj: |
Molecular and Cellular Biology; June 1997, Vol. 17 Issue: 6 p3229-3241, 13p |
| Abstrakt: |
Here we investigate the role of the Raf-1 kinase in transformation by the v-abloncogene. Raf-1 can activate a transforming signalling cascade comprising the consecutive activation of Mek and extracellular-signal-regulated kinases (Erks). In v-abl-transformed cells the endogenous Raf-1 protein was phosphorylated on tyrosine and displayed high constitutive kinase activity. The activities of the Erks were constitutively elevated in both v-raf- and v-abl-transformed cells. In both cell types the activities of Raf-1 and v-raf were almost completely suppressed after activation of the cyclic AMP-dependent kinase (protein kinase A [PKA]), whereas the v-abl kinase was not affected. Raf inhibition substantially diminished the activities of Erks in v-raf-transformed cells but not in v-abl-transformed cells, indicating that v-abl can activate Erks by a Raf-1-independent pathway. PKA activation induced apoptosis in v-abl-transformed cells while reverting v-raf transformation without severe cytopathic effects. Overexpression of Raf-1 in v-abl-transformed cells partially protected the cells from apoptosis induced by PKA activation. In contrast to PKA activators, a Mek inhibitor did not induce apoptosis. The diverse biological responses correlated with the status of c-mycgene expression. v-abl-transformed cells featured high constitutive levels of expression of c-myc, which were not reduced following PKA activation. Myc activation has been previously shown to be essential for transformation by oncogenic Abl proteins. Using estrogen-regulated c-mycand temperature-sensitive Raf-1 mutants, we found that Raf-1 activation could protect cells from c-myc-induced apoptosis. In conclusion, these results suggest (i) that Raf-1 participates in v-abltransformation via an Erk-independent pathway by providing a survival signal which complements c-mycin transformation, and (ii) that cAMP agonists might become useful for the treatment of malignancies where abloncogenes are involved, such as chronic myeloid leukemias. |
| Databáze: |
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