Ras Protects Rb Family Null Fibroblasts from Cell Death

Abstract

The retinoblastoma protein (Rb) controls cell proliferation, differentiation, and senescence and provides an essential tumor suppressive function that cells must eliminate to attain unlimited proliferative potential. Elimination of the Rb pathway also results in apoptosis, however, thereby providing an efficient surveillance mechanism to sense the loss of Rb. To become tumorigenic cells must thus overcome not only Rb function but also the apoptotic response caused by the loss of Rb function. We show that oncogenic Ras (RasV12) potently blocks cell death in Rb family member knockout mouse embryo fibroblasts (TKO cells). Activation of phosphatidylinositol 3-kinase and Raf by oncogenic Ras mediated this protection, implying that multiple Ras effector pathways are required, in concert, for this pro-survival signal. Although activation of Raf by selective Ras mutants protected TKO cells from cell death, pharmacologic inhibition of MEK had little effect on RasV12 protection, suggesting that a Raf-dependent, MEKindependent pathway was important for this effect. We show that this Raf-dependent protection occurred through activation of c-Jun and thus AP-1 activation. These observations could account for the dependence of Ras transformation on c-Jun activity and for the roles of AP-1 in oncogenesis. Our results support the concept of two oncogenic events cooperating to achieve a balance between immortalization and survival.

c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer

“…However, to overcome apoptosis, cells must not only overcome Rb function but also the apoptotic response caused by loss of Rb function. Young and Longmore showed that the oncoprotein Ras protects Rb null fibroblast from cell death and that this relation occurred through the activation of c-Jun and thus AP-1 [27]. The direct relation between AP-1 activation and Rb phosphorylation found in our present study indicates that AP-1 activation might play a role in apoptosis inhibition and supports the hypothesis of 2 cooperating oncogenic events to achieve a balance between immortalization and survival.…”

A Gradient of Epidermal Growth Factor Receptor Signaling Determines the Sensitivity of rbf1 Mutant Cells to E2F-Dependent Apoptosis

“…For example, recent studies have shown that apoptosis in cultured fibroblasts lacking Rb family proteins (TKO) can be suppressed by activation of Ras/Raf (73). Interestingly, a functional homologue of Hid, Smac/Diablo, was recently shown to be a direct target of E2F1 in mammalian cells (69), raising the possibility that mammalian cells may contain a regulatory loop that directly parallels the regulation of Hid.…”

Suppression of PTEN Expression Is Essential for Antiapoptosis and Cellular Transformation by Oncogenic Ras

“…In addition to promoting cell proliferation, oncogenic Ras also shows antiapoptotic effects. In many tumors, activation of Ras correlates with very low rates of apoptosis (15). Moreover, tumor development and maintenance necessitates continued expression of activated Ras to prevent apoptosis: withdrawal of doxycycline-inducible oncogenic Ras expression in transgenic mice bearing melanomas causes apoptosis in both the melanoma and endothelial cells of the tumor (16).…”