Suppression of c-Myc-induced apoptosis by Ras signalling through PI(3)K and PKB

Abstract

The viability of vertebrate cells depends on survival factors which activate signal transduction pathways that suppress apoptosis. Defects in anti-apoptotic signalling pathways are implicated in many pathologies including cancer, in which apoptosis induced by deregulated oncogenes must be forestalled for a tumour to become established. Phosphatidylinositol-3-kinase (PI(3)K) is involved in the intracellular signal transduction of many receptors and has been implicated in the transduction of survival signals in neuronal cells. We therefore examined the role of PI(3)K, its upstream effector Ras, and its putative downstream protein kinase effectors PKB/Akt and p70S6K (ref. 5) in the modulation of apoptosis induced in fibroblasts by the oncoprotein c-Myc. Here we show that Ras activation of PI(3)K suppresses c-Myc-induced apoptosis through the activation of PKB/Akt but not p70S6K. However, we also found that Ras is an effective promoter of apoptosis, through the Raf pathway. Thus Ras activates contradictory intracellular pathways that modulate cell viability. Induction of apoptosis by Ras may be an important factor in limiting the expansion of somatic cells that sustain oncogenic ras mutations.

NF-κB is required for H-ras oncogene induced abnormal cell proliferation and tumorigenesis

“…In contrast to a previous report (Mayo et al, 1997), induction of oncogenic HRas protein had little e ect on cell viability of RIE(iRas)/DN-IkBa cells. Moreover, consistent with the ®ndings that Ras promotes cell survival rather than cell death in epithelial cells (Cardone et al, 1998;Downward, 1998;Kau man-Zeh et al, 1997;Khwaja et al, 1997;Romashkova and Makarov, 1999), H-Ras induction signi®cantly prevented cell death of RIE(iRas)/DN-IkBa cells upon TNF-a treatment as determined by colonigenic assay (Figure 4c). These observations suggest that reduction in cell number of RIE(iRas)/DN-IkBa cells over that of control cells upon Ras induction is due to growth suppression rather than increased cell death.…”

“…The Ras proteins are important signaling molecules that regulate various cellular processes including growth, di erentiation, survival, and senescence (Downward, 1998;Kau man-Zeh et al, 1997;Khwaja et al, 1997;Lin et al, 1998;Lowy et al, 1993;Zhu et al, 1998). In response to external stimuli such as growth factors, Ras activates multiple downstream e ectors that initiate signaling cascades via activation of protein kinases (Lowy et al, 1993;White et al, 1995).…”

Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

“…Hyperactivation of mTORC1 in certain cell types results in suppression of AKT kinase activity through negative feedback, which is reflected by the hypophosphorylation of Thr308 and Ser493 (Harrington et al , 2004; Manning, 2004; Rozengurt et al , 2014). Since AKT has a known anti‐apoptotic activity (Ahmed et al , 1997; Dudek et al , 1997; Kauffmann‐Zeh et al , 1997; Kennedy et al , 1997), a potential inhibition of AKT could be involved in the observed cell death. However, in a panel of BL cell lines, TSC1 knockdown either resulted in an increase in Ser493 phosphorylation or did not change Ser493 phosphorylation of AKT, while we were unable to detect any Thr308 phosphorylation in our assay (Fig EV4A).…”

Specific TrkA survival signals interfere with different apoptotic pathways

“…An anti-apoptotic role of PI3-kinase is further supported by the ®nding that the PI3-kinase-activated serine/threonine kinase Akt/PKB is required for IGF-Iinduced survival of serum-deprived neurones (Dudek et al, 1997) and by the observation that activated Akt/ PKB is su cient to block U.V.-induced apoptosis in ®broblasts (Kulik et al, 1997). Furthermore, activated forms of both PI3-kinase and Akt/PKB suppress c-Myc induced apoptosis in Rat-1MycER TM cells when overexpressed (Kau mann-Zeh et al, 1997).…”