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• W4361255220 abstract "<div>Abstract<p>Expression of mutationally activated <i>RAS</i> is a feature common to the vast majority of human pancreatic adenocarcinomas. RAS elicits its effects through numerous signaling pathways including the RAF→mitogen-activated protein (MAP)/extracellular signal–regulated kinase (ERK) kinase [MEK]→ERK MAP kinase pathway. To assess the role of this pathway in regulating cell proliferation, we tested the effects of pharmacologic inhibition of MEK on human pancreatic cancer cell lines. In eight cell lines tested, MEK inhibition led to a cessation of cell proliferation accompanied by G₀-G₁ cell cycle arrest. Concomitant with cell cycle arrest, we observed induced expression of p27^Kip1, inhibition of cyclin/cyclin-dependent kinase 2 (cdk2) activity, accumulation of hypophosphorylated pRb, and inhibition of E2F activity. Using both antisense and RNA interference techniques, we assessed the role of p27^Kip1 in the observed effects of MEK inhibition on pancreatic cancer cell proliferation. Inhibition of p27^Kip1 expression in Mia PaCa-2 cells restored the activity of cyclin/cdk2, phosphorylation of pRb, and E2F activity and partially relieved the effects of U0126 on pancreatic cancer cell cycle arrest. Consistent with the effects of p27^Kip1 on cyclin/cdk2 activity, inhibition of CDK2 expression by RNA interference also led to G₀-G₁ cell cycle arrest. These data suggest that the expression of p27^Kip1 is downstream of the RAF→MEK→ERK pathway and that the regulated expression of this protein plays an important role in promoting the proliferation of pancreatic cancer cells. Moreover, these data suggest that pharmacologic inhibition of the RAF→MEK→ERK signaling pathway alone might tend to have a cytostatic, as opposed to a cytotoxic, effect on pancreatic cancer cells.</p></div>" @default.
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• W4361255220 date "2023-03-30" @default.
• W4361255220 modified "2023-10-14" @default.
• W4361255220 title "Data from Pharmacologic Inhibition of RAF→MEK→ERK Signaling Elicits Pancreatic Cancer Cell Cycle Arrest Through Induced Expression of p27^Kip1" @default.
• W4361255220 doi "https://doi.org/10.1158/0008-5472.c.6493856" @default.
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