Curcumin shifts RAS-induced pro-proliferative MEK/ERK-signaling toward pro-apoptotic p38MAPK/JNK1-signaling, triggering p53 activation and apoptosis [Cell Biology]

Oncogenic RAS is primarily associated with potent mitogenic ability, and RAS mutants also have an apoptogenic activity, which is poorly understood. Therefore, exploring the signaling circuit that shifts RAS-signals from pro-proliferative to death pathways may provide some molecular clues to the missing link between the mitogenic and apoptogenic mechanisms. Here, we used a systems biology approach exploiting microarray data and employing a mathematical model to better understand the dual role of oncogenic RAS. This approach revealed that a curcumin-based intervention shifts the oncogenic RAS-induced MEK/ERK pro-proliferative pathway toward p38MAPK/JNK1 pro-death signaling. This genotoxic-signal resulted in phosphorylation of p53 at its transactivation domain and in the transcription of BCL2-associated X, apoptosis regulator (BAX) and BCL2-binding component 3 (PUMA) genes, required for p53-dependent apoptosis. Our exploration of this novel signaling network indicated that for oncogenic RAS to induce transformation, RAS-mediated MEK/ERK hyperactivation needs to dominate over its naturally hardwired anti-tumorigenic functions. In summary, this study delineates hitherto unknown mechanisms by which active RAS mutants act as signal-switch molecules that can shift signaling from pro-survival to pro-death circuitry. Our findings highlight potential approaches for tumor control via the differential regulation of different MAPK family members, downstream of RAS, and may, therefore, have therapeutic significance.

from # All Medicine by Alexandros G. Sfakianakis via Alexandros G.Sfakianakis on Inoreader http://ift.tt/2sMncJd
via IFTTT