Minireview: Branded from the StartDistinct Oncogenic Initiating Events May Determine Tumor Fate in the Thyroid
James A. Fagin
Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0547
Address all correspondence and requests for reprints to: James A. Fagin, M.D., Division of Endocrinology and Metabolism, University of Cincinnati College of Medicine, Vontz Center for Molecular Sciences, 3125 Eden Avenue, Cincinnati, Ohio 45267-0547. E-mail: James.Fagin{at}uc.edu.
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ABSTRACT
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Thyroid follicular neoplasms commonly have aneuploidy, presumably due to chromosomal instability. This property is associated with a greater malignant potential and worse prognosis. Recently, there has been considerable progress in our understanding of mechanisms that may account for chromosomal instability in cancer cells. Many tumors with chromosomal instability have abnormalities in the cell cycle checkpoint that monitors the fidelity of mitosis. Mutations of Bub1 or BubR1, genes coding for kinases involved in mitotic spindle assembly checkpoint signaling, are found in a small subset of aneuploid tumors. Other components of protein complexes responsible for attachment of kinetochores to microtubules, or for cohesion between sister chromatids, may also be subject to alterations during tumor progression. Here, we also discuss the evidence that certain oncogenic events, such as Ras mutations, may predispose cells to chromosomal instability by favoring inappropriate posttranslational changes in mitotic checkpoint components through activation of upstream kinases during tumor initiation or progression.
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INTRODUCTION
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NEOPLASMS OF THYROID follicular cells are quite unique, in that tumors with distinct histological characteristics, malignant potential, and degree of differentiation can arise from a single cell type. The lineages giving rise to the major tumor phenotypes, i.e. autonomously functioning thyroid nodules, follicular neoplasms and papillary cancers, appear to diverge from the point of clonal initiation. In this review, the molecular genetic events involved in triggering thyroid tumor formation will be discussed. In particular, mechanisms whereby constitutive activation of particular signal transduction pathways may predispose cells to undergo malignant transformation, whereas others do not, will be addressed.
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Infrequent Malignant Transformation in Tumors Harboring Mutations of Genes that Constitutively Stimulate Adenylyl Cyclase Activity
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Somatic activating mutations of the TSH receptor (TSH-R) or of the guanine nucleotide stimulatory factor
subunit (Gs
) inappropriately induce adenylyl cyclase activity, and promote a relatively unrestrained growth drive in thyroid cells. Moreover, constitutive activation of TSH-R signaling also results in increased expression of thyroid cell differentiated gene products, including thyroglobulin, thyroid peroxidase, and the sodium iodide symporter. Defects in either the TSH-R or Gs
genes account for most autonomously functioning thyroid nodules (1, 2, 3, 4). Although a few thyroid carcinomas with activating point mutations of the TSH-R have been reported (5), these are quite rare (6, 7, 8, 9). Indeed, the consensus from clinical studies is that autonomously functioning thyroid nodules have a low probability of malignant transformation (10). Other human disease paradigms and mouse transgenic models also support the notion that constitutive activation of the adenylyl cyclase signal transduction cascade does not predispose to thyroid cell transformation. Thus, patients with Graves disease or with congenital hyperthyroidism due to germline mutations of the TSH-R do not appear to have a higher rate of thyroid malignancy. Transgenic mice with thyroid specific expression of the A2 adenosine receptor (11), a mutant Gs
(12), or cholera toxin A1 (13) develop thyroid hyperplasia and hyperthyroidism, but not carcinomas.
Thyroid cells adapt to physiological or environmental conditions in which demand for thyroid hormone is increased (i.e. pregnancy, iodine deficiency) through a concerted, TSH-driven increase in both thyroid hormone biosynthesis and cell growth. Thyroid cells somehow are protected from transformation when TSH is the primary growth stimulus, and it is fitting that tumors arising via mutations of genes acting relatively upstream in this pathway are also unlikely to undergo malignant progression. It is not clear why, despite this unremitting mitogenic stimulus, transformation does not take place. As a general principle, cancer development requires accumulation of multiple genetic or epigenetic defects affecting the function of growth promoting, tumor suppressor or survival genes. It is possible that thyroid cells with constitutive adenylyl cyclase activation are less likely to develop additional genetic lesions, either because their genome is less susceptible to mutations (i.e. more stable), or because of lack of cooperativity between mutated genes resulting in constitutive activation of adenylyl cyclase and other common thyroid oncogenes such as Ras or RET/PTC. In support of the latter, activation of oncogenic Ras results in apoptosis in thyroid PCCL3 and Wistar rat thyroid cells (14, 15), particularly if they are grown in the presence of TSH or treated with either forskolin or bromo cAMP (14). These data suggest that if both cAMP and Ras signaling are simultaneously activated in thyroid cells, most cells will die. Experiments demonstrating conflict between cAMP and Ras signaling in thyroid cells were performed after supraphysiological expression of oncogenic Ras, and it is not possible to exclude that high intensity activation of Ras effectors may be required for induction of cell death. However, coexistence of mutations of Ras and either TSH-R or Gs
in the same thyroid tumor clone has not, to our knowledge, been reported.
The same paradigm may not apply when the signal is disrupted through mutation of downstream components of the cAMP pathway. Carney complex, an autosomal dominant disorder associated with cardiac myxomas and endocrine tumors, has recently been reported to be caused in part by inactivating mutations of the gene encoding the regulatory subunit 1A of the cAMP-dependent protein kinase (PKAR1A), resulting in its inappropriate activation (16, 17). These patients develop primarily benign endocrine neoplasms, such as macronodular adrenal hyperplasia, GH-secreting pituitary adenomas, Sertoli cell testicular tumors and autonomously functioning thyroid nodules, but thyroid follicular carcinomas may also be observed (18). Here, despite the fact that the offending stimulus also causes an inappropriate activation of PKA, this distal lesion along the cAMP-dependent signaling network appears to be compatible with cell transformation, albeit with low prevalence. A hypothesis worth testing is whether upstream defects in the cAMP signaling pathway may result in a more integrated stimulus for cell division, whereas more distal activating lesions may be more likely to disrupt cell cycle progression, or generate checkpoint abnormalities that can lead to accumulation of additional gene mutations.
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Ras as a Mutator Gene
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The rate of spontaneous mutations acquired during the natural life span of a cell is low (19, 20, 21). This suggests that one of the early genetic disruptions involved in tumor development may confer cells with a mutator phenotype (22, 23, 24), hence predisposing to the accumulation of additional abnormalities. Activating mutations of Ras are found in both benign and malignant follicular neoplasms, but are more prevalent in the latter (25, 26, 27, 28, 29). By contrast, they are relatively rare in papillary thyroid cancers. They are believed to be one of the early genetic changes in thyroid tumor progression. This conclusion is based on genetic analysis of human tumor samples, and on evidence that thyroid-specific expression of mutant K-Ras in transgenic mice is associated with development of follicular neoplasms (30, 31). In humans, follicular neoplasms (particularly follicular carcinomas) have a much higher rate of allelic losses (32, 33), aneuploidy and chromosomal aberrations than papillary carcinomas (34, 35, 36, 37, 38). These data raise the possibility that oncogenic Ras may serve as a mutator gene in thyroid neoplasms. Here we will review some of the evidence pointing to a role for constitutive Ras activation in the promotion of genomic destabilization and tumor progression.
The mechanisms by which hyperactive Ras causes cell transformation are not well understood. Replacement of a normal H-Ras1 gene by an activated mutant H-Ras by homologous recombination in rat1 fibroblasts is not in itself sufficient to induce transformation, and may require secondary changes such as gene amplification events, including amplification of the mutant Ras allele (39). Induction of expression of the human H-Ras oncogene in p53-null cells leads to premature entry of cells into S phase, increased permissivity for gene amplification, and generation of aberrant chromosomes within a single cell cycle (40, 41, 42). Overexpression of oncogenic Ras has also been shown to produce chromosome aberrations in rat mammary carcinoma cells (43), rat prostatic tumor cells (44), and in a human colon carcinoma cell line (45). Acute H-Rasv12 activation also results in a marked increase in the percentage of thyroid PCCL3 cells with micronuclei, small nuclear-like structures that contain chromosomes or chromosome fragments that form during mitosis as a result of chromosome missegregation (46). This occurs within one or two cell cycles, and appears to be mediated in part by activation of MAPK, as treatment with PD98059 at concentrations verified to selectively inhibit MEK1 (and not PI3K or p38 MAPK) reduces the frequency of micronuclei formation. In addition, doxycycline-inducible expression of a constitutively active MEK1 (mitogen-activated protein kinase-kinase) (which activates ERK1 and 2), but not of a mutant Rac1 (which activates Jun N-terminal kinase and p38 MAPK in these cells), mimics the effects of H-Rasv12. H-Rasv12 and activated MEK1 also induce centrosome amplification, and chromosome misalignment. By contrast, acute activation of RET/PTC1 or RET/PTC3, oncogenes specific for papillary thyroid carcinomas, was entirely without effect. Moreover, treatment of PCCL3 cells with forskolin did not result in chromosomal abnormalities (46). The fact that neither forskolin (which, like mutant forms of the TSH receptor and Gs
, activates adenylate cyclase) nor RET/PTC induced detectable chromosomal changes is consistent with the low frequency of aneuploidy seen in thyroid tumors harboring these latter defects in vivo. An important caveat is that the effects of Ras on chromosomal stability have been examined on immortalized rat thyroid cells. Although these cells have a stable chromosome number, carry no defects of genes known to be associated with genomic instability (i.e. p53 mutations), and are not transformed, they differ in important respects from normal human thyrocytes. Most significantly, the genetic constitution of these immortalized cell lines is unknown because the factors responsible for their long-term survival in culture have not been elucidated. As opposed to rat PCCL3 or FRTL5 cells, primary cultured human thyroid cells proliferate slowly and senesce after a few passages in vitro (47). Infection with replication defective retroviral vectors encoding H-Rasv12 results in increased proliferation, retention of differentiated gene properties, and delayed time to senescence (48). Whether or not oncogenic Ras also induces genomic instability in cultured primary human thyroid cells is unknown. Oncogenic Ras may only induce genomic destabilization in cells with some prior defect. For example, defects in TGFß signaling markedly accentuate the ability of Ras to induce rapid aneuploidy and metastatic potential in mouse keratinocytes (49).
Progression to the malignant state is stimulated by chromosomal instability, yet the events controlled by Ras that may promote acquisition of new chromosomal defects is not clear. Ras genes code for members of a superfamily of ubiquitously expressed signal transduction intermediates that play a central role in the control of cell growth and differentiation. The four mammalian Ras proteins, H-Ras, N-Ras, K-Ras-A, and K-Ras-B, are guanine nucleotide binding proteins with intrinsic low-level GTPase activity, which transduce signals arising from activation of growth factor plasma membrane receptors or G protein-coupled receptors to downstream effector pathways. Ras genes are subject to somatic point mutations in many forms of neoplasia. The mutations introduce structural modifications to the protein that reduce its intrinsic rate of GTP hydrolysis, or enhance its GTP binding affinity, and thus favor its constitutive activation. Many cellular responses to Ras are transduced through the ERK MAPK pathway, resulting from the sequential activation of Raf, MEK, and the p42 and p44 MAPKs. In most cell types, including thyrocytes, Ras also activates the PI3K pathway, as well as RAL guanine nucleotide exchange factors (RAL/GDS) (50, 51). Other responses result from Ras activation of other members of the MAPK superfamily such as Jun N-terminal kinase and p38 MAPK (p38 MAPK). In addition, several members of the Rho family of small GTPases (i.e. RhoA, RhoB, Rac1, Cdc42, and RhoG) have been implicated in Ras-mediated transformation, although the effectors by which Ras feeds into these proteins have not been firmly established (reviewed in Ref. 52). Cell-specific differences in the action of Ras have been attributed in part to preferential signaling through particular downstream intermediates in different cell types. Several authors have reviewed the effects of Ras on cell growth, survival, and differentiation (53, 54, 55). In general, Ras plays an important role integrating mitogenic signals with key determinants of cell cycle progression (56). Most attention has been focused on the role of Ras on events taking place during the G1 phase of the cell cycle. However, recently several groups have pointed to more direct effects of Ras and its downstream effectors on DNA synthesis and mitosis.
A key role for Ras in mitotic spindle assembly has been reported in fission yeast (57). Schizosaccharomyces pombe contain a single Ras homologue, Ras 1 (58). In S. pombe, Ras1 signals through two major pathways that appear to regulate distinct functions: mating (through Byr2, functionally analogous to Raf) and cytoskeletal organization (through Scd1, a putative guanine nucleotide exchange factor activating Cdc42, functionally analogous to a Rho-like GTPase). Scd1 in turn forms a complex with Moe1 and localizes to the spindle during mitosis (59). Double mutants (Moe1 with Ras1 or Scd1) accumulate in early mitosis and have severe spindle assembly defects, suggesting that the Ras1-Scd1 pathway is required for mitotic functions. Interestingly, Scd1 overexpression also results in spindle damage (58). These data point to potential mechanisms by which constitutively activated Ras could disrupt chromosomal stability.
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Role of MAPK in Cell Cycle Progression
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The classical MAPK cascade consists of a series of serine/threonine kinases activated downstream of Ras. Ras-GTP binds to and activates Raf, which directly activates MAPKK1 and MAPKK2 (MEK1 and MEK2). These, in turn, activate the MAPK isoforms ERK1 and ERK2. Activation of MAPK is critical in the control of cellular response to mitogenic signals. The MAPK cascade appears to affect growth through both a nuclear function in transcriptional regulation and cytoskeletal regulated processes (reviewed in Ref. 60). Synthesis of cyclin D1, and its assembly with Cdk4, is rate limiting for growth and activated by ERK (61, 62). Although the role of ERK is believed to be critical, other Ras effectors, such as PI3K, may also contribute to G1-S progression through stabilization of cyclin D1. The active cyclin D-Cdk4 complex phosphorylates and inactivates the growth-suppressing retinoblastoma protein, thus allowing progression into S phase. Recently, ERK has been found to control the activity of carbamoylphosphate synthetase II, an enzyme that catalyzes the initial step in the synthesis of pyrimidine nucleotides (63). This supports a fundamental and more direct role for MAPK in DNA synthesis. Thus, MAPK mediates a coordinate response to extracellular growth signals by regulating some of the key steps in the G0
G1
S stages of the cell cycle.
MAPK activity is also required for G2 progression. Thus, NIH3T3 cells expressing dominant negative MEK1 have reduced growth rate, due primarily to delayed progression through G2/M (64). MAPK is also essential for entry into meiosis I in Xenopus, where it serves as an effector for the germ cell-specific MEK1 activator Mos in the induction of oocyte maturation (65). Information on the role of MAPK in early mitosis of Xenopus embryos differs, however, in important respects from findings in fibroblasts and other cells undergoing somatic mitosis. Thus, in Xenopus embryos MAPK is not required for entry into mitosis and can even inhibit mitotic entry when inappropriately elevated (66). Early embryonic mitotic cycles differ from somatic cycles in that they are rapid and lack G1 and G2 phases. Thus, MAPK may be particularly important in the G2 stage. This is supported by evidence that cells are unable to recover in a timely fashion from ionizing radiation-induced G2 arrest when MEK2 activation is blocked (67).
Finally, recent studies suggest that MAPKs may also play a direct role in mitosis and chromosome segregation. Activated MAPK localizes to kinetochores in early and mid-mitosis, in asters during all stages of mitosis, and in the chromosome midbody in late anaphase (68). It associates with the motor protein centromere protein E and phosphorylates it in vitro. Centromere protein E localizes to kinetochores during prometaphase and regulates attachment of chromosomes to microtubules. MAPK also phosphorylates proteins containing the 3F3/2 phosphoantigen, which recognizes an epitope that disappears with kinetochore attachment to the spindles (69). Evidence for a temporal sequence of localization of activated MAPK in different nuclear compartments during mitosis (68, 69) suggests that phosphorylation-dephosphorylation steps are needed for orderly progression, a step that may be disrupted when MAPK activation is constitutive. The pronounced decrease in chromosome stability after deregulation of activators of MAPK in fibroblasts (70) and thyroid cells (46) supports the notion that this pathway may be of pathogenetic significance in cancer progression (Fig. 1B
).

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Figure 1. Potential Mechanisms Accounting for Chromosomal Instability and Aneuploidy in Human Follicular Neoplasms
Aneuploidy can arise due to defects in a cell cycle checkpoint that monitors the fidelity of mitosis. A, The mitotic checkpoint remains activated during metaphase until sister kinetochores of all duplicated chromosomes have attached to microtubules from opposite spindle poles. The checkpoint works through activation of kinases Bub1, BubR1, Bub3, and Mad1, which are required to prevent entry into anaphase. Mad proteins interact with cdc20 (the mammalian homologue of which is p55Cdc), which in turn regulates the activity of the APC. APC functions as a ubiquitin ligase, which targets destruction of key cell cycle regulatory proteins such as cyclin B1 and securin, thus allowing exit from metaphase and entry into anaphase. Mutations in the genes encoding checkpoint kinases disable the checkpoint and allow cells to progress through the cycle, resulting in errors in chromosome segregation and aneuploidy. Bub1 and BubR1 mutations probably account for only a small proportion of tumors with aneuploidy, but other components of this system may prove to be vulnerable to genetic defects. B, Alternatively, aneuploidy may be favored by inappropriate posttranslational changes in mitotic checkpoint components through activation of upstream kinases during tumor initiation or progression. Oncogenic mutations of Ras result in constitutive MAPK signaling, which causes dysfunction of the DNA damage and mitotic checkpoints in several cell types, including thyroid cells.
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Genetic Instability in Carcinogenesis
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Although the major premise of this review is to examine the possible contribution of tumor initiating oncogenic events to genomic instability in thyroid cells, it is important to provide a broader perspective on the mechanisms by which tumor cells may lose the ability to replicate their genetic material faithfully. Genetic instability is an important driving force underlying cancer development and progression. Different forms of genomic instability arise depending on the nature of the defect responsible for the problem. Lengauer et al. (71) termed the genes giving rise to genomic instability as "caretakers." Inactivation of caretaker genes does not directly promote growth of tumors, but rather does so indirectly by increasing mutation rate. Caretaker gene mutations may be inherited in the germline, and increase cancer predisposition. In hereditary nonpolyposis colorectal cancer, affected patients inherit a mutated copy of one of the genes involved in mismatch DNA repair, giving rise to instability at the nucleotide level (72). Cancers from these patients have microsatellite instability (MIN), and accumulate mutations in numerous oncogenes and tumor suppressor genes (73, 74). Tumors with MIN are usually of either gastrointestinal or endometrial origin (75), and are usually diploid or near-diploid. MIN does not appear to play a major role in pathogenesis of thyroid cancer, as patients with hereditary nonpolyposis colorectal cancer do not have increased predisposition for these tumors. However, sporadic and radiation-induced thyroid neoplasms have been reported to exhibit a low prevalence of MIN (76, 77, 78). Germline mutations of the ataxia-telangiectasia gene, which functions in DNA repair and cell cycle checkpoint control after DNA damage, also confer predisposition to cancer. Recent studies indicate that ataxia-telangiectasia is activated primarily in response to double strand breaks, and that its functional impairment may predispose to translocations and chromosomal abnormalities (79).
Cytogenetic and allelotype studies indicate that most human cancers have either gained or lost whole chromosomes. Recently, the notion that this may due to chromosome instability has gained experimental support, primarily from work performed in colorectal cancer cell lines (80). Moreover, insights into possible mechanisms responsible for this trait are now emerging. Cells are prone to errors during DNA replication and chromosome segregation. To avert this, delays take place at critical junctures of the cell cycle to allow for ordered entry into the process of DNA replication, to provide time for repair of damaged DNA, and ensure proper alignment of chromosomes on the spindle before anaphase. A predisposition to gain or lose whole chromosomes in colorectal cell lines has been linked to abnormalities in the mitotic checkpoint (81), which is activated by the presence of unattached kinetochores (82). In Saccharomyces cerevisiae the budding uninhibited by benzimidazole (BUB1, 2, and 3), and the mitotic-arrest defective 1, 2, and 3 proteins are believed to function as intermediates in signal transduction cascades that are activated by mitotic spindle damage, and delay onset of anaphase (83, 84). This pathway also responds to defects in the structure of centromeres and kinetochores and is thought to be responsible for the mitotic checkpoint activated by unattached or misaligned chromosomes (Fig. 1A
). Mammalian BUB1/BUBR1 and mitotic-arrest defective 2 operate as elements of distinct pathways sensing kinetochore tension and attachment, respectively (85). In Drosophila, animals with near-null mutations of BUB1 die during late larval stages due to mitotic abnormalities indicative of bypass of the mitotic checkpoint function (86). Mutations of a human homologue of the BUB 1 gene have been identified in a subset of colorectal cancer cell lines with chromosomal instability (81), and in one sporadic rectal cancer (87). Somatic mutations of hBUB1 have also been reported in primary lung cancers and lung cancer cell lines (88). However, subsequent studies have not found this to be a common abnormality in these and other tumor types (89, 90). This is also the case in aneuploid thyroid neoplasms and thyroid cancer cell lines with mitotic checkpoint dysfunction, in which mutations of BUB1 or its homologue BUBR1 were largely absent (91). Nevertheless, loss of function of genes coding for other components of the kinetochore-binding complex are candidate mediators of chromosomal instability, and it remains to be determined whether or not somatic mutations of these genes are the dominant cause for this common cancer trait.
An alternative explanation for the chromosomal instability of colorectal cancers has recently been advanced, based on the discovery of a new property of the adenomatous polyposis coli tumor suppressor gene product (APC). APC appears to regulate the assembly of microtubules, the fibers that make up the mitotic spindle. A complex of proteins that includes APC may function as adapters that allow the kinetochore to attach to microtubules. Mutations in APC domains involved in these associations may disrupt normal chromosome alignment and segregation in metaphase, thus predisposing to aneuploidy (reviewed in Ref. 92).
Recently, overexpression of the pituitary tumor transforming gene product (PTTG), the mammalian homolog of the protein securin, has been reported in different tumor types, including pituitary adenomas (93, 94) and thyroid neoplasms (95). Separation of sister chromatids in anaphase is mediated by separase, an endopeptidase that cleaves the chromosomal cohesin SCC1. Separase is in turn inhibited by securin, which is degraded at the metaphase-anaphase transition. Overexpression of PTTG/securin has been found to induce aneuploidy in certain cell types (96). Curiously, mice lacking PTTG are viable, and embryonic PTGG (-/-) fibroblasts have numerous chromosomal abnormalities (97). Thus, factors involved in sister chromatid separation represent yet another putative alternative pathway that when disrupted can result in aneuploidy. So far, there are no reports of tumor-promoting mutations of PTTG/securin, and most of the tumors exhibit primarily higher levels of expression.
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CONCLUSIONS
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Chromosome instability can therefore arise through mutations of "caretaker" genes that are directly involved in the control of mitotic fidelity (Fig. 1A
). An alternative mechanism that might explain the chromosomal instability of certain cancers is through disruption of signaling pathways responsible for transmitting an orderly extracellular mitogenic signal. We have discussed evidence that mutations of oncogenes involved in tumor initiation (i.e. of receptor and non-receptor tyrosine kinases, G proteins, phosphatases, etc.) may result in disorganized signaling at critical stages of the cell cycle, particularly during G2/M, through inappropriate interactions with substrates involved in DNA replication, repair, or chromosome segregation (Fig. 1B
). There is good evidence that abnormal patterns of activation of MAPK during mitosis can be potentially disruptive. No substrate of MAPK has been identified so far that when constitutively phosphorylated will disrupt genomic stability, although new candidates continue to emerge (69, 98, 99). Naturally, these two scenarios are not mutually exclusive, as cancer cells with unstable genomes have a growth advantage, and different defects resulting in the same outcome may be selected during cancer microevolution.
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ACKNOWLEDGMENTS
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I am grateful to Jeffrey Knauf, Bin Ouyang, Jill Shirokawa, Harold Saavedra, Rossella Elisei, and Takeshi Hara for their invaluable contributions to our studies on the role of oncogenic Ras on genomic instability in thyroid cells, and to Peter Stambrook, Erik Knudsen, and Kenji Fukasawa for many helpful discussions.
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FOOTNOTES
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This work was supported in part by NIH Grants CA-72597 and M01-RR08084.
Abbreviations: APC, Anaphase-promoting complex; BUB, budding uninhibited by benzimidazole; Gs
, guanine nucleotide stimulatory factor
subunit; MEK, mitogen-activated protein kinase-kinase (also referred to as MAPKK); MIN, microsatellite instability; PTTG, pituitary tumor transforming gene product; TSH-R, TSH receptor.
Received for publication January 3, 2002.
Accepted for publication January 30, 2002.
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