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

Fikaris, Aphrothiti J.; Lewis, Aurélia E.; Abulaiti, Adili; Tsygankova, Oxana M.; Meinkoth, Judy L.

doi:10.1074/jbc.m606737200

Cited by 32 publications

(26 citation statements)

References 69 publications

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“…Under the conditions we used, activated Ras was expressed at levels 7-to 14-fold over those of endogenous Ras in thyroid cells. Strikingly, even when expressed at the same level as endogenous Ras, RasV12 stimulated cyclin A expression, ATR activity, and apoptosis (29). These data indicate that robust overexpression of Ras is not required for the induction of apoptosis, and that thyroid cells respond to low levels of activated Ras with both cell cycle progression and apoptosis.…”

Section: Discussionmentioning

confidence: 87%

“…These data indicate that robust overexpression of Ras is not required for the induction of apoptosis, and that thyroid cells respond to low levels of activated Ras with both cell cycle progression and apoptosis. Blockade of cell cycle progression by overexpression of p27 inhibited checkpoint activation and apoptosis (29), suggesting that cell cycle progression is a prerequisite to both checkpoint activation and apoptosis. Thus, the induction of apoptosis by Ras in thyroid cells is intricately linked to its ability to stimulate cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

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Ras Induces Chromosome Instability and Abrogation of the DNA Damage Response

Abulaiti

Fikaris²,

Tsygankova³

et al. 2006

Cancer Research

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Ras mutations are frequent in thyroid tumors, the most common endocrine malignancy. The ability of Ras to transform thyroid cells is thought to rely on its mitogenic activity. Unexpectedly, acute expression of activated Ras in normal rat thyroid cells induced a DNA damage response, followed by apoptosis. Notably, a subpopulation of cells evaded apoptosis and emerged with features of transformation, including the loss of epithelial morphology, dedifferentiation, and the acquisition of hormone-and anchorage-independent proliferation. Strikingly, the surviving cells showed marked chromosomal instability. Acutely, Ras stimulated replication stress as evidenced by the induction of ataxia telangiectasia mutated and Rad3-related protein kinase (ATR) activity (Chk1 phosphorylation) and of ;H2A.X, a marker of DNA damage. Despite the activation of a checkpoint, cells continued through mitosis in the face of DNA damage, resulting in an increase in cells harboring micronuclei, an indication of defects in chromosome segregation and other forms of chromosome damage. Cells that survived exposure to Ras continued to exhibit replication stress (ATR activation) but no longer exhibited ;H2A.X or full activation of p53. When rechallenged with Ras or DNA-damaging agents, the surviving cells were more resistant to apoptosis than parental cells. These data show that acute expression of activated Ras is sufficient to induce chromosomal instability in the absence of other signals, and suggest that Ras-induced chromosomal instability arises as a consequence of defects in the processing of DNA damage. Hence, abrogation of the DNA damage response may constitute a novel mechanism for Ras transformation. (Cancer Res 2006; 66(21): 10505-12)

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Ras Induces Chromosome Instability and Abrogation of the DNA Damage Response

Abulaiti

Fikaris²,

Tsygankova³

et al. 2006

Cancer Research

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“…In this context, the Ras pathway has been linked to checkpoint activation in quiescent cells. 32 Therefore, whereas the lethal consequences of combined exposure to DNA-damaging agents and Chk1 inhibitors have been attributed to inappropriate cell-cycle progression, coadministration of MEK1/2 inhibitors may act coordinately with Chk1 inhibitors to promote genotoxicity in both cycling and quiescent cells. The ability of Chk1 inhibitors (eg, UCN-01 and CEP3891) and Chk1 knockdown by shRNA to induce DNA damage has been well documented.…”

Section: Discussionmentioning

confidence: 99%

Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2

Pei

Dai

Youssefian

et al. 2011

Blood

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“…To determine whether the downregulation of Rap1GAP was an early event in Ras transformation, we analyzed the acute effects of oncogenic Ras on Rap1GAP. WRT cells were infected overnight with an adenovirus expressing activated H-Ras (RasV12) (8), and Rap1GAP protein expression was analyzed after 48 h. Rap1GAP expression was extinguished in a dosedependent manner following infection with human H-RasV12 but not LacZ-expressing adenovirus (Fig. 8A).…”

Section: Rap1gap Expression Also Blocked the Invasion Of Rasv12s35 Cementioning

confidence: 99%

“…HA-RasV12 adenovirus was constructed as described previously (8). Adenoviruses expressing Ras effector domain mutants were generated in a similar fashion.…”

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confidence: 99%

Downregulation of Rap1GAP Contributes to Ras Transformation

Tsygankova¹,

Prendergast²,

Puttaswamy³

et al. 2007

Molecular and Cellular Biology

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Although abundant in well-differentiated rat thyroid cells, Rap1GAP expression was extinguished in a subset of human thyroid tumor-derived cell lines. Intriguingly, Rap1GAP was downregulated selectively in tumor cell lines that had acquired a mesenchymal morphology. Restoring Rap1GAP expression to these cells inhibited cell migration and invasion, effects that were correlated with the inhibition of Rap1 and Rac1 activity. The reexpression of Rap1GAP also inhibited DNA synthesis and anchorage-independent proliferation. Conversely, eliminating Rap1GAP expression in rat thyroid cells induced a transient increase in cell number. Strikingly, Rap1GAP expression was abolished by Ras transformation. The downregulation of Rap1GAP by Ras required the activation of the Raf/MEK/extracellular signal-regulated kinase cascade and was correlated with the induction of mesenchymal morphology and migratory behavior. Remarkably, the acute expression of oncogenic Ras was sufficient to downregulate Rap1GAP expression in rat thyroid cells, identifying Rap1GAP as a novel target of oncogenic Ras. Collectively, these data implicate Rap1GAP as a putative tumor/invasion suppressor in the thyroid. In support of that notion, Rap1GAP was highly expressed in normal human thyroid cells and downregulated in primary thyroid tumors. Rap1GAP (30,33) is a member of a family of GTPaseactivating proteins (GAPs) for Rap1/2 GTPases that includes the splice variant Rap1GAPII, SPA-1, and E6TP1. Rap1GAP shares structural similarities with the RhebGAP tuberin. Tuberin is subject to mutational inactivation and loss in tuberous sclerosis, a disease syndrome associated with the formation of multiple benign tumors (15,19,22,37). The downregulation of E6TP1 by human papillomavirus E6 protein is believed to contribute to cervical cancer (10, 11), and an SPA-1 deficiency in mice results in a spectrum of myelodysplastic disorders similar to chronic myelogenous leukemia (13). The rap1GAP gene has been mapped to 1p35-36, a chromosomal region subject to deletion in a variety of human tumors including breast (28) and endocrine (41) neoplasia. Recently, decreased expression and loss of heterozygosity for Rap1GAP were reported for human oropharyngeal squamous cell (43) and pancreatic (21, 42) carcinomas.Rap1GAP is abundant in rat thyroid epithelial cells, where thyroid-stimulating hormone (TSH) regulates Rap1GAP protein stability. The stable overexpression of Rap1GAP in thyroid cells impaired DNA synthesis and the growth rate, and based on this, we suggested that Rap1GAP might function as a tumor suppressor (34). We now provide further support for this idea. Eliminating Rap1GAP expression in differentiated rat thyroid cells induced a transient increase in cell proliferation. Moreover, while highly expressed in normal thyroid follicular cells, Rap1GAP expression was downregulated in primary thyroid tumors and in thyroid carcinoma cell lines. In vitro, decreased expression of Rap1GAP was observed selectively in thyroid carcinoma cell lines that exhibited migratory and inva...

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

Cited by 32 publications

References 69 publications

Ras Induces Chromosome Instability and Abrogation of the DNA Damage Response

Ras Induces Chromosome Instability and Abrogation of the DNA Damage Response

Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2

Downregulation of Rap1GAP Contributes to Ras Transformation

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