The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle.

Denko, Nicholas C.; Giaccia, Amato J.; Stringer, James R.; Stambrook, Peter J.

doi:10.1073/pnas.91.11.5124

Cited by 195 publications

(132 citation statements)

References 28 publications

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“…Indeed, the same HA-RAS allele was previously reported to increase the intracellular level of reactive oxygen species in human fibroblasts, which could trigger various types of DNA damage . Of note, human oncogenic HA-RAS alleles were reported to induce genomic instability in certain cell types (see for example (Denko et al, 1994;Woo and Poon, 2004) but not in others , as in our case with human fibroblasts (Figure 2). The reason of these discrepancies are not known but could rely on cell-type differences, culture conditions and/or levels of Ras activation.…”

Section: Induction Of Different Types Of Trf2 Dysfunction In Telomerimentioning

confidence: 54%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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Although telomere instability is observed in human tumors and is associated with the development of cancers in mice, it has yet to be established that it can contribute to the malignant transformation of human cells. We show here that in checkpoint-compromised telomerase-positive human fibroblasts an episode of TRF2 inhibition promotes heritable changes that increase the ability to grow in soft agar, but not tumor growth in nude mice. This transforming activity is associated to a burst of telomere instability but is independent of an altered control of telomere length. Moreover, it cannot be recapitulated by an increase in chromosome breaks induced by an exposure to cradiations. Since it can be revealed in the context of telomerase-proficient human cells, telomere dysfunction might contribute to cancer progression even at late stages of the oncogenesis process, after the telomerase reactivation step.

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Section: Induction Of Different Types Of Trf2 Dysfunction In Telomerimentioning

confidence: 54%

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

et al. 2005

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“…Several lineage 3 and 5 mice are tumor free, unilateral tumors are common, and tumors appear with long latency. This implies that at least a second genetic event is necessary for the onset of thyroid C-cell tumorigenesis: either directly induced by ras, such as chromosomal breakage and genomic instability leading to mutations in tumor suppressor genes such as p53 or Rb (Denko et al, 1994), or an independent stochastic event occurring by chance with increasing age. The high incidence of MTC in thyroids from rascal transgenic mice but not in any normal littermates would favor a direct linkage between expression of activated ras and development of Ccell tumors.…”

Section: Discussionmentioning

confidence: 99%

Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma

1998

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v-Ha-ras has been demonstrated previously to induce neuroendocrine di erentiation of medullary thyroid carcinoma (MTC, malignant C cell tumor) cell lines. The potential role of ras mediated signaling in neuroendocrine cells in vivo has been investigated by expressing v-Ha-ras under control of the neural/ neuroendocrine speci®c calcitonin/calcitonin gene-related peptide (CGRP) promoter. Five independent mouse lineages were derived following germ line insertion of the transgene. Four of the ®ve lineages consistently express the transgene; neuroendocrine expression is found in three of the ®ve lineages as both spliced and full length messages. Phenotypically, the mice expressing rascal have shortened lifespans primarily due to the high incidence of MTCs between 6 months to a year of age. C-cell hyperplasia is demonstrated in several mice in the absence of gross evidence of tumor formation. Histopathological and ultrastructural analyses demonstrate typical features of MTCs including prominent immunohistochemical staining for calcitonin and dense-core neurosecretory-type granules. In addition, four of 22 tumors co-express thyroglobulin (a non-neuroendocrine follicular epithelial cell marker) and calcitonin (a neuroendocrine marker) in a subset of the tumor cells. The rascal transgenic mouse provides a unique model for investigating the sequential pathogenesis of MTC and possibly also for elucidating the relationship between MTC and mixed medullary-follicular carcinomas.

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“…As damage is present in the chromosomes of cells treated with both nocodazole and z-VAD-fmk, breakage appears to be caspase-independent. Other works have shown that DNA damage can be induced by overexpression of oncogenes such as Myc and Ras (Denko et al, 1994;Felsher and Bishop, 1999;Vafa et al, 2002;Pusapati et al, 2006), suggesting that forced cell cycle entry under inappropriate conditions triggers chromosome breaks. Hence, a variety of signals monitoring cell cycle progression, including mitotic surveillance, may converge to activate chromosome breaks and finally the removal of unwanted cells via the classical p53-dependent apoptotic process.…”

Section: Which Features Trigger Dna Breaks?mentioning

confidence: 99%

Sustained mitotic block elicits DNA breaks: one-step alteration of ploidy and chromosome integrity in mammalian cells

Quignon

Rozier

et al. 2006

Oncogene

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Following prolonged mitotic spindle disruption by microtubule poisons, mammalian cells delay their entry into anaphase, then progressively slip out of mitosis and become tetraploid. Normal cells then stop cycling before S-phase onset, but the mechanisms underlying this arrest are still unclear. Here we show that a double block prevents endo-reduplication. First, cells that exit mitosis without a functional microtubule network are driven toward G0. Reconstitution of the network unmasks a second block that relies on DNA double-strand breaks occurring early in the G1 phase that follows the mitotic block. We propose that a stress signal elicited upon mitotic impairment triggers breakage, which couples the leaky spindle checkpoint to the stringent DNA damage response. Consistent with this finding, cells defective for the damage response continue cycling and acquire, within a single cell cycle, both chromosome rearrangements and abnormal chromosome numbers that remarkably mimic the complex genetic hallmark of tumorigenesis.

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The human Ha-ras oncogene induces genomic instability in murine fibroblasts within one cell cycle.

Abstract: ABSTRACT

Cited by 195 publications

References 28 publications

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

TRF2 inhibition promotes anchorage-independent growth of telomerase-positive human fibroblasts

Expression of v-Ha-ras driven by the calcitonin/calcitonin gene-related peptide promoter: a novel transgenic murine model for medullary thyroid carcinoma

Sustained mitotic block elicits DNA breaks: one-step alteration of ploidy and chromosome integrity in mammalian cells

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