Activation of p53-mediated cell cycle checkpoint in response to micronuclei formation

1998 ◽  
Vol 111 (7) ◽  
pp. 977-984
Author(s):  
A.A. Sablina ◽  
G.V. Ilyinskaya ◽  
S.N. Rubtsova ◽  
L.S. Agapova ◽  
P.M. Chumakov ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Cell Activation ◽  
P53 Gene ◽  
Cell Cycle Checkpoint ◽  
Abnormal Chromosome ◽  
Brdu Incorporation ◽  
Temperature Sensitive ◽  
Cells With Micronuclei ◽  
Cycle Checkpoint

Inactivation of p53 tumor-suppressor leads to genetic instability and, in particular, to accumulation of cells with abnormal numbers of chromosomes. In order to better define the role of p53 function in maintaining genome integrity we investigated the involvement of p53 in the control of proliferation of micronucleated cells resulting from abnormal chromosome segregation. Using cell lines expressing temperature-sensitive (ts) p53 or containing p53 genetic suppressor element (p53-GSE) we showed that inhibition of p53 function increases the frequency of cells with micronuclei. Immunofluorescence study revealed that in REF52 cell cultures with both spontaneous and colcemid-induced micronuclei the proportion of p53-positive cells is considerably higher among micronucleated variants as compared with their mononuclear counterparts. Analysis of 12(1)ConA cells expressing the beta-galactosidase reporter gene under the control of a p53-responsive promoter showed activation of p53-regulated transcription in the cells with micronuclei. Importantly, the percentage of cells manifesting specific p53 activity in colcemid-treated cultures increased with an augmentation of the number of micronuclei in the cell. Activation of p53 in micronucleated cells was accompanied by a decrease in their ability to enter S-phase as was determined by comparative analysis of 5-bromodeoxyuridine (5-BrdU) incorporation by the cells with micronuclei and their mononuclear counterparts. Inhibition of p53 function in the cells with tetracycline-regulated p53 gene expression, as well as in the cells expressing ts-p53 or p53-GSE, abolished cell cycle arrest in micronucleated cells. These results along with the data showing no increase in the frequency of chromosome breaks in REF52 cells after colcemid treatment suggest the existence of p53-mediated cell cycle checkpoint(s) preventing proliferation of micronucleated cells derived as a result of abnormal chromosome segregation during mitosis.

Cell Cycle Checkpoint Genes and Aneuploidy: A Short Review

2001 ◽  
Vol 2 (2) ◽  
pp. 171-180 ◽  
Author(s):  
William Kearns ◽  
Johnson Liu
Keyword(s):  
Cell Cycle ◽  
Short Review ◽  
Cell Cycle Checkpoint ◽  
Cycle Checkpoint ◽  
Checkpoint Genes

scholarly journals Acceleration or Brakes: Which Is Rational for Cell Cycle-Targeting Neuroblastoma Therapy?

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 750
Author(s):  
Kiyohiro Ando ◽  
Akira Nakagawara
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Cell Cycle Progression ◽  
Parp Inhibitors ◽  
Cell Cycle Checkpoint ◽  
Mitotic Catastrophe ◽  
Malignant Neoplasms ◽  
Checkpoint Kinases ◽  
Molecular Features ◽  
Cycle Checkpoint

Unrestrained proliferation is a common feature of malignant neoplasms. Targeting the cell cycle is a therapeutic strategy to prevent unlimited cell division. Recently developed rationales for these selective inhibitors can be subdivided into two categories with antithetical functionality. One applies a “brake” to the cell cycle to halt cell proliferation, such as with inhibitors of cell cycle kinases. The other “accelerates” the cell cycle to initiate replication/mitotic catastrophe, such as with inhibitors of cell cycle checkpoint kinases. The fate of cell cycle progression or arrest is tightly regulated by the presence of tolerable or excessive DNA damage, respectively. This suggests that there is compatibility between inhibitors of DNA repair kinases, such as PARP inhibitors, and inhibitors of cell cycle checkpoint kinases. In the present review, we explore alterations to the cell cycle that are concomitant with altered DNA damage repair machinery in unfavorable neuroblastomas, with respect to their unique genomic and molecular features. We highlight the vulnerabilities of these alterations that are attributable to the features of each. Based on the assessment, we offer possible therapeutic approaches for personalized medicine, which are seemingly antithetical, but both are promising strategies for targeting the altered cell cycle in unfavorable neuroblastomas.

scholarly journals A DNA-Damage-Induced Cell Cycle Checkpoint in Arabidopsis

Genetics ◽  
2003 ◽  
Vol 164 (1) ◽  
pp. 323-334
Author(s):  
S B Preuss ◽  
A B Britt
Keyword(s):  
Cell Cycle ◽  
Gamma Radiation ◽  
Cell Cycle Progression ◽  
Cell Cycle Checkpoint ◽  
Phase Cell ◽  
Cycle Arrest ◽  
Cycle Checkpoint ◽  
Radiation Induced ◽  
High Doses ◽  
Regulation Of Cell Cycle

Abstract Although it is well established that plant seeds treated with high doses of gamma radiation arrest development as seedlings, the cause of this arrest is unknown. The uvh1 mutant of Arabidopsis is defective in a homolog of the human repair endonuclease XPF, and uvh1 mutants are sensitive to both the toxic effects of UV and the cytostatic effects of gamma radiation. Here we find that gamma irradiation of uvh1 plants specifically triggers a G2-phase cell cycle arrest. Mutants, termed suppressor of gamma (sog), that suppress this radiation-induced arrest and proceed through the cell cycle unimpeded were recovered in the uvh1 background; the resulting irradiated plants are genetically unstable. The sog mutations fall into two complementation groups. They are second-site suppressors of the uvh1 mutant's sensitivity to gamma radiation but do not affect the susceptibility of the plant to UV radiation. In addition to rendering the plants resistant to the growth inhibitory effects of gamma radiation, the sog1 mutation affects the proper development of the pollen tetrad, suggesting that SOG1 might also play a role in the regulation of cell cycle progression during meiosis.

scholarly journals Centrosome Dynamics and Its Role in Inflammatory Response and Metastatic Process

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 629
Author(s):  
Massimo Pancione ◽  
Luigi Cerulo ◽  
Andrea Remo ◽  
Guido Giordano ◽  
Álvaro Gutierrez-Uzquiza ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Rho Gtpases ◽  
Human Cancer ◽  
Genetic Disorders ◽  
Cell Cycle Checkpoint ◽  
Animal Cells ◽  
Normal Tissues ◽  
Checkpoint Pathway ◽  
New Findings ◽  
Cycle Checkpoint

Metastasis is a process by which cancer cells escape from the location of the primary tumor invading normal tissues at distant organs. Chromosomal instability (CIN) is a hallmark of human cancer, associated with metastasis and therapeutic resistance. The centrosome plays a major role in organizing the microtubule cytoskeleton in animal cells regulating cellular architecture and cell division. Loss of centrosome integrity activates the p38-p53-p21 pathway, which results in cell-cycle arrest or senescence and acts as a cell-cycle checkpoint pathway. Structural and numerical centrosome abnormalities can lead to aneuploidy and CIN. New findings derived from studies on cancer and rare genetic disorders suggest that centrosome dysfunction alters the cellular microenvironment through Rho GTPases, p38, and JNK (c-Jun N-terminal Kinase)-dependent signaling in a way that is favorable for pro-invasive secretory phenotypes and aneuploidy tolerance. We here review recent data on how centrosomes act as complex molecular platforms for Rho GTPases and p38 MAPK (Mitogen activated kinase) signaling at the crossroads of CIN, cytoskeleton remodeling, and immune evasion via both cell-autonomous and non-autonomous mechanisms.

Advancing maternal age compromises control of cell cycle checkpoint for aneuploidies in human embryos cultured in vitro

2002 ◽  
Vol 78 ◽  
pp. S181
Author(s):  
H Asakura ◽  
K.P Katayama ◽  
E.F Stehlik ◽  
J.C Stehlik ◽  
K Winchester-Peden
Keyword(s):  
Cell Cycle ◽  
Maternal Age ◽  
Cell Cycle Checkpoint ◽  
Human Embryos ◽  
Cycle Checkpoint
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