p53 Is Necessary for the Apoptotic Response Mediated by a Transient Increase of Ras Activity

Ma, Peihong; Magut, Maureen; Chen, Xinbin; Chen, Chang Yan

doi:10.1128/mcb.22.9.2928-2938.2002

Cited by 18 publications

(22 citation statements)

References 48 publications

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“…Our previous studies also demonstrated cooperation between oncogenic Ras and PKC. For instance, when endogenous PKC activity is suppressed, the increase in Ras activity is capable of inducing apoptosis in various types of cells, including lung cancer cells (20,40). In this investigation, we again showed such cooperation; after the ablation of PKC activity by GO6976, there were no MTX-resistant colonies observed from nicotinetreated RLE/E6 cells as well as no colonies formed in soft agar.…”

Section: Discussionsupporting

confidence: 55%

Persistent Nicotine Treatment Potentiates Amplification of the Dihydrofolate Reductase Gene in Rat Lung Epithelial Cells as a Consequence of Ras Activation

Guo

Chu

Abbeyquaye

et al. 2005

Journal of Biological Chemistry

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Although nicotine has been suggested to promote lung carcinogenesis, the mechanism of its action in this process remains unknown. The present investigation demonstrates that the treatment of rat lung epithelial cells with nicotine for various periods differentially mobilizes multiple intracellular pathways. Protein kinase C and phosphoinositide 3-OH-kinase are transiently activated after the treatment. Also, Ras and its downstream effector ERK1/2 are activated after long term exposure to nicotine. The activation of Ras by nicotine treatment is responsible for the subsequent perturbation of the methotrexate (MTX)-mediated G 1 cell cycle restriction as well as an increase in production of reactive oxygen species. When p53 expression is suppressed by introducing E6, persistent exposure to nicotine enables dihydrofolate reductase gene amplification in the presence of methotrexate (MTX) and the formation of the MTX-resistant colonies. Altering the activity of phosphoinositide 3-OH-kinase has no effect on dihydrofolate reductase amplification. However, the suppression of protein kinase C dramatically affects the colony formation in soft agar. Thus, our data suggest that persistent exposure to nicotine perturbs the G 1 checkpoint and causes DNA damage through the increase of the production of reactive oxygen species. However, a third element rendered by loss of p53 is required for the initiation of the process of gene amplification. Under p53-deficient conditions, the establishment of a full oncogenic transformation, in response to long term nicotine exposure, is achieved through the cooperation of multiple signaling pathways.

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Section: Discussionsupporting

confidence: 55%

Persistent Nicotine Treatment Potentiates Amplification of the Dihydrofolate Reductase Gene in Rat Lung Epithelial Cells as a Consequence of Ras Activation

Guo

Chu

Abbeyquaye

et al. 2005

Journal of Biological Chemistry

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“…Suppression of JNK abolishes this phosphorylation, and partially blocks the apoptotic process mediated by a transient increase of Ras activity. She concluded that different mechanisms are used by short-and long-term activation of Ras to initiate apoptosis and that the status of p53 may contribute to such differences (30).…”

Section: Stress Signaling In Apoptosismentioning

confidence: 99%

Recent Advances in Stress Signaling in Cancer

Morin¹,

Huot²

2004

Cancer Research

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This meeting brought together some of the world's leading scientists in the field of stress signaling, apoptosis, and cancer. This resulted in a productive interaction that updated our current knowledge on "Stress Signaling in Cancer." It comes out that subtle disturbances in cell signaling can be associated with and even lead to cancer. As a corollary, it appears that correcting the signaling defects associated with cancer constitutes a new approach to the treatment and control of neoplastic diseases. The meeting also raised several questions that should be addressed. In particular, it is of the utmost importance to better understand the mechanisms that underlie the specificity of the cellular response with regard to different ligands. For example, why does Gadd45b prevent apoptotic cell death in response to tumor necrosis factor ␣, whereas it favors apoptosis after transforming growth factor ␤ (E. De

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“…[21][22][23][24][25][26]. Therefore, we asked what effect the expression of oncogenic Ras would have on the cell death that results from functional loss of Rb family members, an essential step in tumorigenesis.…”

Section: Oncogenic Ras Protects Against Loss-of-rb-mediated Cellmentioning

confidence: 99%

Ras Protects Rb Family Null Fibroblasts from Cell Death

Young

Longmore

2004

Journal of Biological Chemistry

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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.

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p53 Is Necessary for the Apoptotic Response Mediated by a Transient Increase of Ras Activity

Cited by 18 publications

References 48 publications

Persistent Nicotine Treatment Potentiates Amplification of the Dihydrofolate Reductase Gene in Rat Lung Epithelial Cells as a Consequence of Ras Activation

Persistent Nicotine Treatment Potentiates Amplification of the Dihydrofolate Reductase Gene in Rat Lung Epithelial Cells as a Consequence of Ras Activation

Recent Advances in Stress Signaling in Cancer

Ras Protects Rb Family Null Fibroblasts from Cell Death

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