Enhanced sensitivity to apoptosis in Ras-transformed thyroid cells

Cheng, Guanjun; Meinkoth, Judy L.

doi:10.1038/sj.onc.1204928

Cited by 20 publications

(11 citation statements)

References 37 publications

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“…2B). In further support of this, deprivation of attachment by trypsin-EDTA release failed to induce CDK-2 activity, 4 and plating cells on agarose-coated dishes failed to induce apoptosis (32). Most importantly, CDK-2 activity was not impaired by QVD (Fig.…”

Section: Ras-induced Apoptosis Ismentioning

confidence: 84%

Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling

Fikaris

Lewis²,

Abulaiti

et al. 2006

Journal of Biological Chemistry

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Genetic evidence indicates that Ras plays a critical role in the initiation and progression of human thyroid tumors. Paradoxically, acute expression of activated Ras in normal rat thyroid cells induced deregulated cell cycle progression and apoptosis. We investigated whether cell cycle progression was required for Ras-stimulated apoptosis. Ras increased CDK-2 activity following its introduction into quiescent cells. Apoptotic cells exhibited a sustained increase in CDK-2 activity, accompanied by the loss of CDK-2-associated p27. Blockade of Ras-induced CDK-2 activity and S phase entry via overexpression of p27 inhibited apoptosis. Inactivation of the retinoblastoma protein in quiescent cells through expression of HPV-E7 stimulated cell cycle progression and apoptosis, indicating that deregulated cell cycle progression is sufficient to induce apoptosis. Ras failed to induce G 1 phase growth arrest in normal rat thyroid cells. Rather, Ras-expressing thyroid cells progressed into S and G 2 phases and evoked a checkpoint response characterized by the activation of ATR. Ras-stimulated ATR activity, as evidenced by Chk1 and p53 phosphorylation, was blocked by p27, suggesting that cell cycle progression triggers checkpoint activation, likely as a consequence of replication stress. These data reveal that Ras is capable of inducing a DNA damage response with characteristics similar to those reported in precancerous lesions. Our findings also suggest that the frequent mutational activation of Ras in thyroid tumors reflects the ability of Ras-expressing cells to bypass checkpoints and evade apoptosis rather than to simply increase proliferative potential.

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Section: Ras-induced Apoptosis Ismentioning

confidence: 84%

Ras Triggers Ataxia-telangiectasia-mutated and Rad-3-related Activation and Apoptosis through Sustained Mitogenic Signaling

Fikaris

Lewis²,

Abulaiti

et al. 2006

Journal of Biological Chemistry

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“…Signaling from the small GTPase, Ras, has been under intense investigation in the past decade due to the importance of the Ras as a switch mediating pathways that control transcriptional activation of genes governing such critical and diverse cellular functions as proliferation, development, differentiation, and apoptosis (Ayllon and Rebollo, 2000;Crespo and Leon, 2000;Kolch, 2000;Brooks et al, 2001;Cheng and Meinkoth, 2001;Fedorov et al, 2001;Pervaiz et al, 2001;Radhika and Dhanasekaran, 2001). It is not surprising, therefore, that deregulation of Ras activity by mutation may have such profound consequences for the cell.…”

Section: Introductionmentioning

confidence: 99%

Opposite effects of Ha-Ras and Ki-Ras on radiation-induced apoptosis via differential activation of PI3K/Akt and Rac/p38 mitogen-activated protein kinase signaling pathways

et al. 2004

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It has been well known that Ras signaling is involved in various cellular processes, including proliferation, differentiation, and apoptosis. However, distinct cellular functions of Ras isozymes are not fully understood. Here we show the opposing roles of Ha-Ras and Ki-Ras genes in the modulation of cell sensitivity to ionizing radiation. Overexpression of active isoform of Ha-Ras (12V-HaRas) in Rat2 cells increases resistance to the ionizing radiation. Constitutive activation of phosphoinositide-3-kinase (PI3K) and Akt is detected specifically in 12V-HaRas-overexpressing cells. The specific PI3K inhibitor LY294002 inhibits PI3K/Akt signaling and potentiates the radiation-induced apoptosis, suggesting that activation of the PI3K/Akt signaling pathway is involved in the increased radio-resistance in cells overexpressing 12V-Ha-Ras. Overexpression of activated Ki-Ras (12V-KiRas), on the other hand, markedly increases radiation sensitivity. The p38 mitogen-activated protein kinase (MAPK) activity is selectively enhanced by ionizing radiation in cells overexpressing 12V-Ki-Ras. The specific p38 MAPK inhibitor, PD169316, or dominant-negative p38 MAPK decreases radiation-induced cell death. We further show that the mechanism that underlies potentiation of cell death in cells overexpressing 12V-Ki-Ras involves Bax translocation to the mitochondrial membrane. Elevated Bax translocation following ionizing irradiation in 12V-Ki-Ras-overexpressing cells is completely inhibited by PD169316 or dominant-negative p38 MAPK. In addition, introduction of cells with RacN17, a dominant-negative mutant of Rac, resulted in a marked inhibition of radiation-induced Bax translocation and apoptotic cell death as well as p38 MAPK activation. Taken together, these findings explain the opposite effects of Ha-Ras and Ki-Ras on modulation of radiosensitivity, and suggest that differential activation of PI3K/Akt and Rac/p38 MAPK signaling by Ha-Ras and Ki-Ras may account for the opposing response to the ionizing radiation. These data provide an explanation for the diverse biological functions of Ras isozymes, and partly accounts for the differential response of transformed cells to anticancer treatments.

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“…Unlike many cells, exposure of human (Gire et al, 2000) or rat (Cheng and Meinkoth, 2001) thyroid cells to inhibitors of PI3K or MEK failed to stimulate cell death, even under conditions of prolonged growth factor withdrawal. In contrast, treatment with cytokines (Saavedra, in preparation) or NO donors such as SNP stimulated apoptotic cell death.…”

Section: Discussionmentioning

confidence: 99%

“…DNA was isolated using the Easy-DNA kit from Invitrogen (San Diego, CA, USA) and analysed by agarose (1.2%) gel electrophoresis as described previously (Cheng and Meinkoth, 2001). …”

Section: Dna Ladderingmentioning

confidence: 99%