Chromosomes and Neoplasia

Harnden, D. G.; Taylor, Alexander M.

doi:10.1007/978-1-4615-8276-2_1

Cited by 14 publications

(10 citation statements)

References 233 publications

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“…Therefore, the dependence of mitosis on completion of DNA synthesis (and on intact chromosomes) is due in part to the RAD9 checkpoint. In multicellular organisms, the importance of an analogous checkpoint that ensures the order of mitosis and DNA replication and the fidelity of chromosome segregation may be important in prevention of aneuploidy and the resulting abnormal, uncontrolled or cancerous cell growth (14).…”

Section: Discussionmentioning

confidence: 99%

Characterization of RAD9 of Saccharomyces cerevisiae and evidence that its function acts posttranslationally in cell cycle arrest after DNA damage.

Weinert¹,

Hartwell²

1990

Mol. Cell. Biol.

205

151

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In eucaryotic cells, incompletely replicated or damaged chromosomes induce cell cycle arrest in G2 before mitosis, and in the yeast Saccharomyces cerevisiae the RAD9 gene is essential for the cell cycle arrest (T. A. Weinert and L. H. Hartwell, Science 241:317-322, 1988). In this report, we extend the analysis of RAD9-dependent cell cycle control. We found that both induction of RAD9-dependent arrest in G2 and recovery from arrest could occur in the presence of the protein synthesis inhibitor cycloheximide, showing that the mechanism of RAD9-dependent control involves a posttranslational mechanism(s). We have isolated and determined the DNA sequence of the RAD9 gene, confirming the DNA sequence reported previously (R. H. Schiestl, P. Reynolds, S. Prakash, and L. Prakash, Mol. Cell. Biol. 9:1882-1886). The predicted protein sequence for the Rad9 protein bears no similarity to sequences of known proteins. We also found that synthesis of the RAD9 transcript in the cell cycle was constitutive and not induced by X-irradiation. We constructed yeast cells containing a complete deletion of the RAD9 gene; the rad9 null mutants were viable, sensitive to X-and UV irradiation, and defective for cell cycle arrest after DNA damage. Although Rad+ and rad9A cells had similar growth rates and cell cycle kinetics in unirradiated cells, the spontaneous rate of chromosome loss (in unirradiated cells) was elevated 7-to 21-fold in rad9A cells. These studies show that in the presence of induced or endogenous DNA damage, RAD9 is a negative regulator that inhibits progression from G2 in order to preserve cell viability and to maintain the fidelity of chromosome transmission.In eucaryotic cells, DNA replication must be complete and chromosomes must be undamaged for an interphase cell to progress into mitosis. Inhibition of DNA synthesis or induction of DNA damage leads to arrest of the cell cycle before mitosis and chromosome segregation (1,4,5,18,31,54). Studies from several organisms suggest that cell cycle arrest after DNA damage is due to extrinsic control mechanisms rather than to a structural requirement of mitosis for intact chromosomes (reviewed in reference 18). For example, caffeine treatment of mammalian cells antagonizes the arrest induced either by DNA damage or by inhibition of DNA synthesis and causes the arrested interphase cells to enter mitosis prematurely (6,44,48,52 [36,46]. We recognize the ambiguity and refer to the RAD9-dependent control as regulating the progression from G2 to anaphase.) In contrast to the arrest response of wild-type cells, X-irradiated rad9 cells proceed without delay through G2 and chromosome segregation, and the cells die. Yeast cells with a temperature-sensitive defect in DNA ligase (cdc9 mutants) also die more rapidly at the restrictive temperature in rad9 cells than in RAD9 cells (18,47). The defect in rad9 mutant cells appears to be solely in cell cycle control because rad9 cells survive X-irradiation if progression from G2 is delayed by treatment with a microtubule inhibitor; the drug-im...

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Section: Discussionmentioning

confidence: 99%

Characterization of RAD9 of Saccharomyces cerevisiae and evidence that its function acts posttranslationally in cell cycle arrest after DNA damage.

Weinert¹,

Hartwell²

1990

Mol. Cell. Biol.

205

151

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“…The first of these was certainly the lack of cancer-specific karyotypes [Rous, 1959;Bauer, 1963;Braun, 1969;DiPaolo, 1975;Nowell, 1976;Harnden and Taylor, 1979;Cram et al, 1983;Sandberg, 1990;Harris, 1995;Heim and Mitelman, 1995]. According to Rous, discoverer of Rous sarcomas virus, "Persistent search has been made, ever since Boveri's time, for chromosome alterations which might prove characteristic of the neoplastic state-all to no purpose" [Rous, 1959].…”

Section: Introductionmentioning

confidence: 99%

“…Yes No 4 (6) Too many and abnormal centrosomes Yes No 5 (7) Karyotypic or "genetic" instability Yes No 6 (8) Immortality in vitro and on transplantation Yes No 7 (9) Clonal origin Yes Yes 9 (10) Non-clonal karyotypes and phenotypes, including non-clonal onco-and tumor suppressor genes [Hansemann, 1890;Hansemann, 1897;Hauser, 1903;Hauschka, 1961;Bauer, 1963;Braun, 1969;Pitot, 1986]; 2 [Boveri, 1914;Bauer, 1963;Cairns, 1978;Pitot, 1986]; 3 [Busch, 1974;Augenlicht et al, 1987;Zhang et al, 1997;Duesberg et al, 1999;Rasnick and Duesberg, 1999]; 4 [Bauer, 1963;Caspersson et al, 1963;Busch, 1974;Rasnick and Duesberg, 1999]; 5 [Brinkley and Goepfert, 1998;Lingle et al, 1998;Pihan et al, 1998;Duesberg, 1999]; 6 [Bauer, 1963;Braun, 1969;DiPaolo, 1975;Nowell, 1976;Harnden and Taylor, 1979;Pitot, 1986;Sandberg, 1990;Heim and Mitelman, 1995;Duesberg et al, 1998;Heppner and Miller, 1998;Rasnick and Duesberg, 1999]; 7 [Levan and Biesele, 1958;Saksela and Moorhead, 1963;Hayflick, 1965;Cairns, 1978;Harris, 1995]; 8 [Foulds, 1965;…”

Section: Introductionmentioning

confidence: 99%

Aneuploidy, the somatic mutation that makes cancer a species of its own

Duesberg

Rasnick

2000

Cell Motil. Cytoskeleton

206

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“…In contrast, many cell lines derived from CFU-FV-A could be induced to undergo erythroid differentiation by purified human Epo, whereas cell lines derived from CFU-FV-P did not Karyotypic analysis. Increases in chromosomal abnormalities are frequently associated with the progression of neoplastic diseases (19,23,41 (32).…”

Section: Discussionmentioning

confidence: 99%

Clonal analysis of the late stages of erythroleukemia induced by two distinct strains of Friend leukemia virus.

et al. 1981

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We observed striking differences between the tumorigenic colony-forming cells present in the spleens of mice late after infection with the anemia-inducing strain of Friend leukemia virus (strain FV-A) and those present after infection with the polycythemia-inducing strain (strain FV-P). Cells within primary colonies derived from FV-A-and FV-P-transformed cells (CFU-FV-A and CFU-FV-P, respectively) contained hemoglobin and spectrin, indicating that the CFU-FV-A and CFU-FV-P were transformed erythroid progenitor cells. The proportion of cells containing hemoglobin was relatively high (>25%) in newly isolated cell lines , derived from CFU-FV-P colonies, whereas cell lines derived from CFU-FV-A colonies had only low levels (O to 2%) of hemoglobin-containing cells. A high proportion of the cell lines derived from CFU-FV-A colonies responded to pure erythropoietin and accumulated spectrin and hemoglobin, whereas the cell lines derived from CFU-FV-P colonies did not. A cytogenetic analysis indicated that primary CFU-FV-P colony cells were diploid, whereas chromosomal aberrations were observed in the immediate progeny of CFU-FV-A. The presence of unique chromosomal markers in the majority of the cells within individual colonies derived from CFU-FV-A suggested that these colonies originated from single cells. Finally, leukemic progenitor cells transformed by strain FV-A appeared to have an extensive capacity to self-renew (i.e., form secondary colonies in methylcellulose), whereas a significant proportion of the corresponding cells transformed by strain FV-P did not. In addition, the self-renewal capacity of both CFU-FV-A and CFU-FV-P increased as the disease progressed. From these observations, we propose a model for the multistage nature of Friend disease; this model involves clonal evolution and expansion from a differentiating population with limited proliferative capacity to a population with a high capacity for selfrenewal and proliferation.Two distinct isolates of Friend leukemia virus have been described, and both of these isolates induce rapid splenomegaly and erythroleukemia in susceptible adult mice. The original isolate (strain FV-A) (11) induces anemia, whereas the later isolate (strain FV-P), which was derived from stocks of FV-A (38), induces polycythemia. In addition to these opposite effects on the levels of erythrocytes in the peripheral blood, the diseases induced by FV-A and FV-P can be distinguished by the different responses of erythroid progenitor cells to the hormnone erythropoietin (Epo). Erythropoiesis in FV-A-infected mice appears to remain under the control of Epo in vivo (49), whereas erythropoiesis in FV-P-infected t Present address:

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Chromosomes and Neoplasia

Cited by 14 publications

References 233 publications

Characterization of RAD9 of Saccharomyces cerevisiae and evidence that its function acts posttranslationally in cell cycle arrest after DNA damage.

Characterization of RAD9 of Saccharomyces cerevisiae and evidence that its function acts posttranslationally in cell cycle arrest after DNA damage.

Aneuploidy, the somatic mutation that makes cancer a species of its own

Clonal analysis of the late stages of erythroleukemia induced by two distinct strains of Friend leukemia virus.

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