Ras mediates cell survival by regulating tuberin

Abstract

Mutational activation of Ras promotes oncogenesis by controlling cell cycle regulation and cell survival. Rasmediated activation of both, the PI3K/AKT pathway and the MEK/ERK pathway, can trigger downregulation of the function of tuberin to block the activities of mTOR and p70S6K. Here we demonstrate that Ras-induced cell survival is accompanied by upregulation of p70S6K activity. Ras harbors the potential to negatively affect tuberin-induced apoptosis and p70S6K inactivation. These effects of Ras were found to depend on its potential to regulate the MEK/ERK pathway. Experiments using tuberin-negative fibroblasts revealed that the potential of Ras to counteract apoptosis depends on functional tuberin. Taken together, we provide evidence that the function of Ras to trigger inactivation of tuberin plays a major role in the regulation of cell survival upon mutational activation of the oncogene Ras. This is the first description of a functional interaction between the tumor suppressor tuberin and the oncogene Ras in regulating apoptosis.

Liquiritigenin exhibits antitumour action in pituitary adenoma cells via Ras/ERKs and ROS-dependent mitochondrial signalling pathways

“…The current study showed that LQ significantly reduced the expressions of Ras, the phosphorylation of ERKs and nucleus translocation of P‐ERKs. As Ras is an essential mediator of upstream of ERKs and cancer cell apoptotic death, our results suggest that Ras/ERKs cascade signalling is an alternative pathway involved in the antitumour effect of LQ against pituitary adenoma. On the other hand, inhibition of ERKs activity results in G1 phase arrest and a down‐regulation of the expression of the mitochondrial function‐associated proteins Bcl‐2 and Bcl‐xL .…”

Chemoattractant-Induced Signaling via the Ras–ERK and PI3K–Akt Networks, along with Leukotriene C4 Release, Is Dependent on the Tyrosine Kinase Lyn in IL-5– and IL-3–Primed Human Blood Eosinophils

“…The small MW G protein Ras has been previously shown to be critical for IL-5-induced ERK1/2 phosphorylation in human blood eosinophils (32) and is a known upstream effector of both the ERK1/2 and PI3K-Akt cascades (59–61). A previous report from our lab has showed that Ras activity is up-regulated in concert with the enhanced ERK1/2 phosphorylation in fMLP-stimulated human blood eosinophils upon IL-5 priming (62), and the data in the present report (Figs.…”

Marked Activity of Irinotecan and Rapamycin Combination toward Colon Cancer Cells In vivo and In vitro Is Mediated through Cooperative Modulation of the Mammalian Target of Rapamycin/Hypoxia-Inducible Factor-1α Axis

“…PI3K activation may modulate the response to mTOR inhibitors depending on the genetic context. Interestingly, it has recently been shown that Ras also regulates the mTOR pathway and that Ras-induced cell survival is accompanied by up-regulation of p70 S6 kinase activity (24). To further explore the mechanisms underlying the reduced sensitivity of HCT-116 cells to rapamycin, the hotspot mutation sites of the PI3Ka catalytic subunit (exons 9 and 20) and K-Ras (exon 1) in HCT-116 and HT-29 cells were sequenced (Fig.…”

“…Different processes leading to mTOR activation includes loss of PTEN function (37,38), mutation or amplification of the PI3K p110 catalytic unit (39), amplification of one of the Akt isoenzymes (40), and inactivation of mTOR-regulatory proteins such as tuberous sclerosis 1 or 2 (41). More recently, it has been shown that the mTOR pathway can also be activated by oncogenes including Ras, which may act through both PI3K-dependent and PI3K-independent mechanisms (24,42).…”