Cell cycle targets of Ras/Raf signalling

Abstract

The regulation of cell proliferation in multicellular organisms is a complex process, which is primarily regu-lated by external growth factors provided by surrounding cells. Once induced to proliferate, the passage through the mitotic cell cycle is directed by the components of the so called cell cycle machinery. Over the last years research on growth factor signaltransduction and the components of the cell cycle system has lead to a detailed knowledge of the mechanisms by which growth factors transmit their signals and of the relationship between the components of the cell cycle machinery. The remaining question how the growth factor mediated signal-transduction cascades couple with the cell cycle regulators has recently been a focus of interest.Keywords: Ras; Raf; cell cycleThe Ras GTP-binding protein and Raf kinases have a central role in transmitting growth factor-triggered signals. The Ras protein is an important e ector of growth factor receptors and activates di erent signaltransduction cascades (Daum et al., 1994;Avruch et al., 1994;Rodriguez Viciana et al., 1996;Symons, 1996). One of these is the Ras/Raf/Mek/Erk cascade (Daum et al., 1994). By direct interaction the Ras protein targets the Raf kinase to the plasma membrane where the catalytic activity of the kinase becomes activated. Subsequently Raf stimulates the Mek kinase by phosphorylation, which then phosphorylates and activates the Erk kinases. The Erk kinases shuttle into the nucleus and induce the activity of transcription factors. By employing constitutively active and dominant negative mutants of the Ras and Raf proteins it has been shown that the Ras/Raf signaltransduction cascade plays a crucial role in the regulation of cell proliferation by growth factors (Mulcahy et al

A Short Hairpin DNA Analogous to miR-125b Inhibits C-Raf Expression, Proliferation, and Survival of Breast Cancer Cells

“…Both ErbB2 and C-Raf can regulate the expression of cyclin D1, a key regulator of the G 1 checkpoint in the cell cycle (25,57). Consistently, ODN-Raf diminished cyclin D1 level.…”

“…Deregulation of this pathway is characteristic for many human tumors. Accordingly, activating mutants of Raf proteins and upstream elements such as receptor tyrosine kinases and Ras proteins were identified in these tumors (24)(25)(26)(27)(28).…”

Cooperative cell transformation by Myc/Mil(Raf) involves induction of AP-1 and activation of genes implicated in cell motility and metastasis

“…A deregulated Ras/Raf(Mil)/MEK/ ERK signaling pathway is involved in many cancer types and leads to the activation of nuclear effectors at the transcriptional or post-transcriptional level, for instance by phosphorylation of critical gene regulators. A prototypic nuclear effector of this signaling cascade is AP-1 (Rapp et al, 1994;Suzuki et al, 1994;Eferl and Wagner, 2003), but there is also evidence that other transcription factors like Myc could participate in this mitogenic signaling pathway (Kerkhoff and Rapp, 1998 although the molecular mechanisms of Myc activation remain still obscure. There is clear evidence that Myc and Mil(Raf) act synergistically in cell transformation.…”

“…Figure 1c). A possibly complex mechanism of synergism could be based on the acceleration of cell division and proliferation by v-Myc, strongly enhancing the v-Mil(Raf)-induced aberrant mitogenic signaling pathway (Kerkhoff and Rapp, 1998;Grandori et al, 2000).…”

Ras-dependent carbon metabolism and transformation in mouse fibroblasts

“…Ras proteins are small GTPases able to bind either GTP ('on' state) or GDP ('off' state), thus acting as intracellular molecular switches (Lowy and Willumsen, 1993) linking growth factor activation to the cell cycle machinery (Kerkhoff and Rapp, 1998;Roovers and Assoian, 2000). The level of the active GTP-bound form results from the balance of the competing activity of GTPase-activating proteins (GAP) and guanine nucleotide exchange factors (GEF) (Feig, 1994;Reuther and Der, 2000).…”