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

Abstract

The inactivation of retinoblastoma (Rb) family members sensitizes cells to apoptosis. This cell death affects the development of mutant animals and also provides a critical constraint to the malignant potential of Rb mutant tumor cells. The extent of apoptosis caused by the inactivation of Rb is highly cell type and tissue specific, but the underlying reasons for this variation are poorly understood. Here, we characterize a specific time and place during Drosophila melanogaster development where rbf1 mutant cells are exquisitely sensitive to apoptosis. During the third larval instar, many rbf1 mutant cells undergo E2F-dependent cell death in the morphogenetic furrow. Surprisingly, this pattern of apoptosis is not caused by inappropriate cell cycle progression but instead involves the action of Argos, a secreted protein that negatively regulates Drosophila epidermal growth factor receptor (EGFR [DER]) activity. Apoptosis of rbf1 mutant cells is suppressed by the activation of DER, ras, or raf or by the inactivation of argos, sprouty, or gap1, and inhibition of DER strongly enhances apoptosis in rbf1 mutant discs. We show that RBF1 and a DER/ras/raf signaling pathway cooperate in vivo to suppress E2F-dependent apoptosis and that the loss of RBF1 alters a normal program of cell death that is controlled by Argos and DER. These results demonstrate that a gradient of DER/ras/raf signaling that occurs naturally during development provides the contextual signals that determine when and where the inactivation of rbf1 results in dE2F1-dependent apoptosis.

Deregulated G1/S control and energy stress contribute to the synthetic lethal interactions between inactivation ofRBandTSC1/TSC2

“…Clones of cells overexpressing dE2f1,dDp in eye discs show a pattern of apoptosis near the MF (Fig. 3C,C9) similar to rbf mutation (Moon et al, 2006;Tanaka-Matakatsu et al, 2009). Coexpression of Rheb with dE2f1,dDp significantly increases the level of cell death in these eye discs, particularly in clones anterior to the MF ( Fig.…”

“…This is likely due to the fact that additional cell-intrinsic and extrinsic factors also influence the level of synergistic cell death. For example, it has been shown that Hid protein is preferentially accumulated near the MF in rbf-mutant eye discs (Tanaka-Matakatsu et al, 2009) and that epidermal growth factor receptor (EGFR) signaling, which is an important survival signal in the posterior of the eye disc (Yang and Baker, 2003), negatively regulates rbf-mediated cell death (Moon et al, 2006).…”

Role ofDrosophilaretinoblastoma protein instability element in cell growth and proliferation

“…[18][19][20] While hid appears to be responsible for apoptosis in the eye discs, loss of Rbf1 also causes apoptosis in wing imaginal discs. [21][22][23] At the same time, expression of Rbf1 can also induce apoptosis in proliferating cells, an effect that is suppressed by ectopic E2F. 18 The "threshold" model of E2F Surface area was measured using WINGMACHINE software.…”

Novel regulation and functional interaction of polycistronic miRNAs

“…In rbf mutant eye discs, E2F activity is derepressed, which leads to EGFR-dependent ectopic cell death in a narrow stripe anterior to the morphogenetic furrow (MF) of larval eye discs ( Fig. 3C; Moon et al 2006). Overexpression of miR-998 was previously shown to suppress apoptosis, whereas the loss of mir-998 enhanced apoptosis in the MF of rbf mutant larval eye discs.…”