Oncogenic and wild-type Ras play divergent roles in the regulation of mitogen-activated protein kinase signaling
Menée sur des lignées cellulaires, cette étude met en évidence les rôles différents joués par les isoformes oncogéniques et non mutées du gène Ras dans la régulation de la voie de signalisation MAPK
H-Ras, K-Ras and N-Ras regulate cellular growth and survival and are often activated by somatic mutation in human tumors. Although oncogenic lesions occur in a single Ras isoform within individual tumors, it is unclear whether the remaining wild-type isoforms play supporting roles in tumor growth. Here, we show that oncogenic and wild-type Ras isoforms play independent and non-redundant roles within the cell. Oncogenic Ras regulates basal effector pathway signaling, while wild-type Ras mediates signaling downstream of activated receptor tyrosine kinases (RTKs). We show that both are necessary for exponential growth of Ras mutant cell lines. Furthermore, we show that oncogenic Ras desensitizes signaling from epidermal growth factor receptor (EGFR). Depletion of oncogenic Ras with siRNA oligonucleotides relieves this negative feedback, leading to hyperactivation of EGFR and wild-type Ras signaling. Consistent with this model, combining oncogenic Ras depletion with EGFR inhibition potently increases cell death.
Cancer Discovery 2012