title: Ras-dependent apoptosis correlates with persistent activation of stress-activated protein kinases and induction of isoform(s) of Bcl-x.
abstract: Ras proteins are signal transducers for many cellular responses. However, it is not well established whether Ras-signaling also contributes to apoptosis. We have constructed H-RasR12-transformed Rat1 fibroblasts using tetracycline operator/repressor (TetO/TetR)-based conditional vectors. Rat1/TetO-RasR12 (Rat1-Ras) cells produced high levels of H-RasR12 protein and exhibited oncogenic transformation. Treatment of Rat1-Ras cells with 0.1% serum triggered massive apoptosis. Rat1-Ras cells expressed increased basal activities of extracellular response kinase (ERK) and p46/p54 stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK). Interestingly, Ras-dependent apoptosis correlated with further persistent activation of both p46 and p54 SAPK/JNK and concurrent inhibition of ERK. Differential modulation of SAPK/JNK and ERK was not detected in tetracycline-treated cells that did not commit apoptosis. Furthermore, two Bcl-x related proteins of 15 kDa and 18 kDa were highly induced in apoptotic Rat1-Ras cells. Our results establish a direct role for Ras in apoptosis, and suggest a functional relationship between H-Ras, SAPK/JNK, ERK and Bcl-x in regulating apoptosis.
authors.affiliation: Oncology Research Program, Preclinical Research, Sandoz Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
authors.forename: K
authors.initials: K
authors.lastname: Yu
authors.forename: Y N
authors.initials: YN
authors.lastname: Chen
authors.forename: C P
authors.initials: CP
authors.lastname: Ravera
authors.forename: W
authors.initials: W
authors.lastname: Bayona
authors.forename: C M
authors.initials: CM
authors.lastname: Nalin
authors.forename: R
authors.initials: R
authors.lastname: Mallon