The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition

Abstract

The Ras-dependent extracellular signal-regulated kinase (ERK)1/2 mitogen-activated protein (MAP) kinase pathway plays a central role in cell proliferation control. In normal cells, sustained activation of ERK1/ERK2 is necessary for G1-to S-phase progression and is associated with induction of positive regulators of the cell cycle and inactivation of antiproliferative genes. In cells expressing activated Ras or Raf mutants, hyperactivation of the ERK1/2 pathway elicits cell cycle arrest by inducing the accumulation of cyclin-dependent kinase inhibitors. In this review, we discuss the mechanisms by which activated ERK1/ERK2 regulate growth and cell cycle progression of mammalian somatic cells. We also highlight the findings obtained from gene disruption studies.

Resveratrol Inhibits Proliferation and Survival of Epstein Barr Virus–Infected Burkitt's Lymphoma Cells Depending on Viral Latency Program

“…Although p38 MAPK is generally believed to be a kinase that mediates cell death, ERK1/2 MAPK pathways have been shown to promote survival and cell growth (36). Our findings indicating inhibition of ERK1/2 activity and the concomitant activation of p38 signaling cascade confirm the opposite effects these kinases play in determining cell survival/death and may account for the observed antiproliferative activity of resveratrol on BL cells.…”

“…Our findings indicating inhibition of ERK1/2 activity and the concomitant activation of p38 signaling cascade confirm the opposite effects these kinases play in determining cell survival/death and may account for the observed antiproliferative activity of resveratrol on BL cells. It has been proposed that ERK1/2 kinases regulate G 1 phase progression through various mechanisms including cyclin D1 induction, enhanced c-myc protein stability, p27 downregulation, and decreased expression of antiproliferative genes (36,37). Although cyclin D1 protein levels were barely detectable in resveratrol-treated BL cells, our results showing c-myc suppression and the increment of p27 protein levels suggest the involvement of ERK1/2 pathway in mediating resveratrol-induced cell-cycle arrest.…”

Multiple effects of TRAIL in human carcinoma cells: Induction of apoptosis, senescence, proliferation, and cytokine production

“…Cytokines by binding to their cognate receptors on tumor cells could provide proliferative signals that could counter apoptotic effects of TRAIL. In addition, TRAIL-induced stimulation of tumor cell proliferation could be a result of involvement of other mechanisms, such as activation cyclin kinases and stimulation cell cycle [25][26][27]. Moreover, activation of downstream caspases could trigger cellcycle arrest and development of senescence in some of the surviving cells (Figure 8).…”

“…TRAIL signaling via cognate receptors activates various signaling pathways, including MAPKs, PKB/Akt-and NF-κB-signaling cascades that could ultimately activate cyclin kinases and stimulate cell cycle [25][26][27].…”

Effects of bufalin on the proliferation of human lung cancer cells and its molecular mechanisms of action

“…In the present study, suppression of the pathways of p44/42 and p38 MAPKs, pAkt and p-NF-jB by bufalin could be responsible for the reduction of COX-2 expression in A549 cells. The ERK1/2 and p38 MAPK signaling pathways can be activated in response to a diverse range of extracellular stimuli including mitogens, growth factors, and cytokines (Baccarini 2005;Meloche and Pouysségur 2007;Roux and Blenis 2004) and are important targets in the diagnosis and treatment of cancer (Roberts and Der 2007). Suppression of the activated EGFR and ERK1/2 and p38 MAPKs as well as Akt signaling pathways led to inhibition of the proliferation of A549 cells (Baldys et al 2007;Nguyen et al 2004;Recchia et al 2009;Su et al 2010).…”