Activation of p53-mediated cell cycle checkpoint in response to micronuclei formation (original) (raw)
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Specific loss of apoptotic but not cell - cycle arrest function in a human tumor derived p53 mutant
1996
The p53 tumor-suppressor gene product is frequently inactivated in malignancies by point mutation. Although most tumor-derived p53 mutants show loss of sequence specific transcriptional activation, some mutants have been identified which retain this activity. One such mutant, p53175P, is defective for the suppression of transformation in rodent cells, despite retaining the ability to suppress the growth of p53-null human cells. We now demonstrate that p53175P can induce a cell-cycle arrest in appropriate cell types but shows loss of apoptotic function. Our results therefore support a direct role of p53 transcriptional activation in mediating a cell-cycle arrest and demonstrate that such activity is not sufficient for the full apoptotic response. These data suggest that either p53 can induce apoptosis through a transcriptionally independent mechanism, a function lost by p53175P, or that this mutant has specifically lost the ability to activate genes which contribute to cell death, despite activation of genes responsible for the G1 arrest. This dissociation of the cell-cycle arrest and apoptotic activities of p53 indicates that inactivation of p53 apoptotic function without concomitant loss of growth inhibition can suffice to relieve p53-dependent tumor-suppression in vivo and thereby contribute to tumor development.
Oncogene, 1997
The radiation response was investigated in two lymphoblastoid cell lines (LBC) derived from families with heterozygous germ-line missense mutations of p53 at codon 282 (LBC282) and 286 (LBC286), and compared to cells with wt/wt p53(LBC-N). By gel retardation assays, we show that p53-containing nuclear extracts from irradiated LBC282 and LBC286 markedly dier in their ability to bind to a p53 DNA consensus sequence, the former generating a shifted band whose intensity is 30 ± 40% that of LBC-N, the latter generating an almost undetectable band. Unlike LBC286, which fail to arrest in G 1 after irradiation, LBC282 have an apparently normal G 1 /S checkpoint, as they arrest in G 1 , like LBC-N. While in LBC-N, accumulation of p53 and transactivation of p21 WAF1 increase rapidly and markedly by 3 h after exposure to g-radiation, in LBC286 there is only a modest accumulation of p53 and a signi®cantly delayed and quantitatively reduced transactivation of p21 WAF1 . Instead, in LBC282 while p53 levels rise little after irradiation, p21 WAF1 levels increase rapidly and signi®cantly as in normal LBC. Apoptotic cells present 48 h after irradiation account for 32% in LBC-N, 8 ± 9% in LBC282 and 5 ± 7% in LBC286, while the dose of g-radiation required for killing 50% of cells (LD 50 ) is 400 rads, 1190 rads and 3190 rads, respectively, hence indicating that the heterozygous mutations of p53 at codon 282 aects radioresistance and survival, but not the G 1 /S cell cycle control. In all LBC tested, radiationinduced apoptosis occurs in all phases of the cell cycle and appears not to directly involve changes in the levels of the apoptosis-associated proteins bcl-2, bax and mcl-1. Both basal as well as radiation-induced p53 and p21 WAF1 proteins are detected by Western blotting of FACS-puri®ed G 1 , S and G 2 /M fractions from the three cell lines. p34 CDC2-Tyr15 , the inactive form of p34 CDC2 kinase phosphorylated on Tyr15, is found in S and G 2 /M fractions, but not in G 1 . However, 24 h after irradiation, its levels in these fractions diminish appreciably in LBC-N but not in the radioresistant LBC286 and LBC282. Concomitantly, p34 CDC2 histone H1 kinase activity increases in the former, but not in the latter cell lines, hence suggesting a role for this protein in radiationinduced cell death. Altogether, this study shows that, in cells harbouring heterozygous mutations of p53, the G 1 checkpoint is not necessarily disrupted, and this may be related to the endogenous p53 heterocomplexes having lost or not the capacity to bind DNA (and therefore transactivate target genes). Radiation-induced cell death is not cell cycle phase speci®c, does not involve the regulation of bcl-2, bax or mcl-1, but is associated with changes in the phosphorylation state and activation of p34 CDC2 kinase.
DNA damage and p53-mediated cell cycle arrest: A reevaluation
Proceedings of the National Academy of Sciences, 1996
Most mammalian cells exhibit transient delays in the G 1 and G 2 phases of the cell cycle after treatment with radiation or radiomimetic compounds. p53 is required for the arrest in G 1 , which provides time for DNA repair. Recently, a role of p53 in the G 2 ͞M transition has also been suggested. However, it has been reported that the presence of functional p53 does not always correlate with the induction of these checkpoints. To precisely assess the role of p53 in activating cell cycle checkpoints and in cell survival after radiation, we studied the response of two isogenic human fibrosarcoma cell lines differing in their p53 status (wild type or mutant). We found that when irradiated cells undergo a wild-type p53-dependent G 1 arrest, they do not subsequently arrest in G 2. Moreover, wild-type p53 cells irradiated past the G 1 checkpoint arrest in G 2 but do not delay in the subsequent G 1 phase. Furthermore, in these cell lines, which do not undergo radiation-induced apoptosis, the wild-type p53 cell line exhibited a greater radioresistance in terms of clonogenic survival. These results suggest that the two checkpoints may be interrelated, perhaps through a control system that determines, depending on the extent of the damage, whether the cell needs to arrest cell cycle progression at the subsequent checkpoint for further repair. p53 could be a crucial component of this control system.
The cellular response to p53: the decision between life and death
Oncogene, 1999
The p53 tumor suppressor protein plays a crucial role in regulating cell growth following exposure to various stress stimuli. p53 induces either growth arrest, which prevents the replication of damaged DNA, or programmed cell death (apoptosis), which is important for eliminating defective cells. Whether the cell enters growth arrest or undergoes apoptosis, depends on the ®nal integration of incoming signals with antagonistic eects on cell growth. Many factors aect the cellular response to activated p53. These include the cell type, the oncogenic status of the cell with emphasis on the Rb/E2F balance, the extracellular growth and survival stimuli, the intensity of the stress signals, the level of p53 expression and the interaction of p53 with speci®c proteins. p53 is regulated both at the levels of protein stability and biochemical activities. This complex regulation is mediated by a range of viral and cellular proteins. This review discusses this intriguing complexity which aects the cell response to p53 activation.
The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis
1994
The p53 tumour-suppressor gene is mutated in 60% of human tumours, and the product of the gene acts as a suppressor of cell division. It is thought that the growth-suppressive effects of p53 are mediated through the transcriptional transactivation activity of the protein. Overexpression of the p53 protein results either in arrest in the GI phase of the cell cycle or in the induction of apoptosis. Both the level of the protein and its transcriptional transactivation activity increase following treatment of cells with agents that damage DNA, and it is thought that p53 acts to protect cells against the accumulation of mutations and subsequent conversion to a cancerous state. The induction of p53 levels in cells exposed to gamma-irradiation results in cell cycle arrest in some cells (fibroblasts) and apoptosis in others (thymocytes). Cells lacking p53 have lost this cell cycle control and presumably accumulate damage-induced mutations that result in tumorigenesis. Thus, the role of p53 in suppressing tumorigenesis may be to rescue the cell or organism from the mutagenic effects of DNA damage. Loss of p53 function accelerates the process of tumorigenesis and alters the response of cells to agents that damage DNA, indicating that successful strategies for radiation therapy may well need to take into account the tissue of origin and the status of p53 in the tumour.
P53 Protein and Its Fundamental Role in the Cell Cycle, Apoptosis and Cancer
Enciclopédia Biosfera, 2018
P53 is activated in response to DNA damage, hypoxia, oncogenesis expression to promote the cell cycle checkpoints, DNA repair, cell senescence and apoptosis. These activities are important for the suppression of tumor formation and mediate cellular responses that are related to the cell cycle control, being the key element and also the main obstacle to the suppression of tumors. A better understanding of the apoptotic mechanism of p53 may promote the development of in vitro and in vivo assays, contributing to improve cancer diagnosis and prognosis and also helping with the deployment of rational strategies that advance the treatment therapies. In this way, this review is intended to present the effects of p53 protein on cells and show how it works on the activation of specific genes to promote the cell control and regulation and clarify the mysteries evolving the cell regulation mediated by p53 protein.