An accelerated senescence response to radiation in wild-type p53 glioblastoma multiforme cells

2006 ◽  
Vol 105 (1) ◽  
pp. 111-118 ◽  
Author(s):  
Quincy A. Quick ◽  
David A. Gewirtz
Keyword(s):  
Glioblastoma Multiforme ◽  
Growth Arrest ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Viable Cell Number ◽  
Mutant P53 ◽  
Wild Type ◽  
Fractionated Radiotherapy ◽  
Accelerated Senescence ◽  
Wild Type P53 ◽  
U87 Cells

Object Radiotherapy is one of the few treatment options available for glioblastoma multiforme (GBM); however, the basis for its overall ineffectiveness in GBM is not fully understood. The present study was designed to explore the nature of the response to ionizing radiation in GBM cells to gain insight into the basis for the general failure of radiotherapy in the treatment of this disease. Methods The response to fractionated radiotherapy was examined in GBM cell lines with differing p53 status. A viable cell number was determined during an 8-day period; accelerated senescence was based on β-galactosidase staining and cell morphology; apoptosis was evaluated by the terminal deoxynucleotidyl transferase–mediated deoxyuridine triphosphate nick-end labeling assay and fluorescence-activated cell-sorter analysis, whereas the expression of cell-cycle regulatory proteins was monitored by Western blot analysis. Based on clonogenic survival, the wild-type p53 U87 cells and mutant p53 T98 cells demonstrated essentially identical sensitivity to fractionated radiotherapy; however, neither cell line underwent apoptosis, and the primary response to irradiation was growth arrest. The wild-type p53 GBM cells showed clear evidence of accelerated senescence in response to irradiation. In contrast, senescence was not evident in mutant p53 GBM cells or GBM cells in which p53 function was abrogated by the viral E6 protein. The T98 (mutant p53) cells demonstrated a relatively robust proliferative recovery whereas both the rate and extent of recovery were attenuated in the wild-type p53 U87 cells. Conclusions Both accelerated senescence and conventional growth arrest are likely to represent alternative responses to apoptosis in irradiated GBM cells.

scholarly journals Mutant p53 tumor suppressor alleles release ras-induced cell cycle growth arrest.

1991 ◽  
Vol 11 (3) ◽  
pp. 1344-1352 ◽  
Author(s):  
G G Hicks ◽  
S E Egan ◽  
A H Greenberg ◽  
M Mowat
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Growth Regulation ◽  
Growth Arrest ◽  
Mutant P53 ◽  
Wild Type ◽  
Type Activity ◽  
Wild Type P53 ◽  
Negative Growth ◽  
P53 Genes

Overexpression of an activated ras gene in the rat embryo fibroblast line REF52 results in growth arrest at either the G1/S or G2/M boundary of the cell cycle. Both the DNA tumor virus proteins simian virus 40 large T antigen and adenovirus 5 E1a are able to rescue ras induced lethality and cooperate with ras to fully transform REF52 cells. In this report, we present evidence that the wild-type activity of the tumor suppressor gene p53 is involved in the negative growth regulation of this model system. p53 genes encoding either a p53Val-135 or p53Pro-193 mutation express a highly stable p53 protein with a conformation-dependent loss of wild-type activity and the ability to eliminate any endogenous wild-type p53 activity in a dominant negative manner. In cotransfection assays, these mutant p53 genes are able to rescue REF52 cells from ras-induced growth arrest, resulting in established cell lines which express elevated levels of the ras oncoprotein and show morphological transformation. Full transformation, as assayed by tumor formation in nude mice, is found only in the p53Pro-193-plus-ras transfectants. These cells express higher levels of the ras protein than do the p53Val-135-plus-ras-transfected cells. Transfection of REF52 cells with ras alone or a full-length genomic wild-type p53 plus ras results in growth arrest and lethality. Therefore, the selective event for p53 inactivation or loss during tumor progression may be to overcome a cell cycle restriction induced by oncogene overexpression (ras). These results suggest that a normal function of p53 may be to mediate negative growth regulation in response to ras or other proliferative inducing signals.

Mutant p53 tumor suppressor alleles release ras-induced cell cycle growth arrest

1991 ◽  
Vol 11 (3) ◽  
pp. 1344-1352
Author(s):  
G G Hicks ◽  
S E Egan ◽  
A H Greenberg ◽  
M Mowat
Keyword(s):  
Cell Cycle ◽  
Tumor Suppressor ◽  
Growth Regulation ◽  
Growth Arrest ◽  
Mutant P53 ◽  
Wild Type ◽  
Type Activity ◽  
Wild Type P53 ◽  
Negative Growth ◽  
P53 Genes

Overexpression of an activated ras gene in the rat embryo fibroblast line REF52 results in growth arrest at either the G1/S or G2/M boundary of the cell cycle. Both the DNA tumor virus proteins simian virus 40 large T antigen and adenovirus 5 E1a are able to rescue ras induced lethality and cooperate with ras to fully transform REF52 cells. In this report, we present evidence that the wild-type activity of the tumor suppressor gene p53 is involved in the negative growth regulation of this model system. p53 genes encoding either a p53Val-135 or p53Pro-193 mutation express a highly stable p53 protein with a conformation-dependent loss of wild-type activity and the ability to eliminate any endogenous wild-type p53 activity in a dominant negative manner. In cotransfection assays, these mutant p53 genes are able to rescue REF52 cells from ras-induced growth arrest, resulting in established cell lines which express elevated levels of the ras oncoprotein and show morphological transformation. Full transformation, as assayed by tumor formation in nude mice, is found only in the p53Pro-193-plus-ras transfectants. These cells express higher levels of the ras protein than do the p53Val-135-plus-ras-transfected cells. Transfection of REF52 cells with ras alone or a full-length genomic wild-type p53 plus ras results in growth arrest and lethality. Therefore, the selective event for p53 inactivation or loss during tumor progression may be to overcome a cell cycle restriction induced by oncogene overexpression (ras). These results suggest that a normal function of p53 may be to mediate negative growth regulation in response to ras or other proliferative inducing signals.

scholarly journals Activated H-ras rescues E1A-induced apoptosis and cooperates with E1A to overcome p53-dependent growth arrest.

1995 ◽  
Vol 15 (8) ◽  
pp. 4536-4544 ◽  
Author(s):  
H J Lin ◽  
V Eviner ◽  
G C Prendergast ◽  
E White
Keyword(s):  
Cell Proliferation ◽  
Cell Death ◽  
Dna Synthesis ◽  
Growth Arrest ◽  
Mutant P53 ◽  
Permissive Temperature ◽  
Wild Type ◽  
Wild Type P53 ◽  
Dependent Growth ◽  
Induced Apoptosis

The adenovirus E1A oncogene products stimulate DNA synthesis and cell proliferation but fail to transform primary baby rat kidney (BRK) cells because of the induction of p53-mediated programmed cell death (apoptosis). Overexpression of dominant mutant p53 (to abrogate wild-type p53 function) or introduction of apoptosis inhibitors, such as adenovirus E1B 19K or Bcl-2 oncoproteins, prevents E1A-induced apoptosis and permits transformation of BRK cells. The ability of activated Harvey-ras (H-ras) to cooperate with E1A to transform BRK cells suggests that H-ras is capable of overcoming the E1A-induced, p53-dependent apoptosis. We demonstrate here that activated H-ras was capable of suppressing apoptosis induced by E1A and wild-type p53. However, unlike Bcl-2 and the E1B 19K proteins, which completely block apoptosis but not p53-dependent growth arrest, H-ras expression permitted DNA synthesis and cell proliferation in the presence of high levels of wild-type p53. The mechanism by which H-ras regulates apoptosis and cell cycle progression is thereby strikingly different from that of the E1B 19K and Bcl-2 proteins. BRK cells transformed with H-ras and the temperature sensitive murine mutant p53(val 135), which lack E1A, underwent growth arrest at the permissive temperature for wild-type p53. p53-dependent growth arrest, however, could be relieved by E1A expression. Thus, H-ras alone was insufficient and cooperation of H-ras and E1A was required to override growth suppression by p53. Our data further suggest that two complementary growth signals from E1A plus H-ras can rescue cell death and thus permit transformation.

scholarly journals Site-specific binding of wild-type p53 to cellular DNA is inhibited by SV40 T antigen and mutant p53.

1992 ◽  
Vol 6 (10) ◽  
pp. 1886-1898 ◽  
Author(s):  
J Bargonetti ◽  
I Reynisdottir ◽  
P N Friedman ◽  
C Prives
Keyword(s):  
Specific Binding ◽  
T Antigen ◽  
Mutant P53 ◽  
Wild Type ◽  
Sv40 T Antigen ◽  
Site Specific ◽  
Wild Type P53 ◽  
Cellular Dna

Human p53 and CDC2Hs genes combine to inhibit the proliferation of Saccharomyces cerevisiae

1992 ◽  
Vol 12 (3) ◽  
pp. 1357-1365
Author(s):  
J M Nigro ◽  
R Sikorski ◽  
S I Reed ◽  
B Vogelstein
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Growth Inhibition ◽  
Mammalian Cells ◽  
P53 Protein ◽  
Inducible Promoter ◽  
Mutant P53 ◽  
Wild Type ◽  
Growth Inhibitory Activity ◽  
Wild Type P53 ◽  
P53 Genes

Human wild-type and mutant p53 genes were expressed under the control of a galactose-inducible promoter in Saccharomyces cerevisiae. The growth rate of the yeast was reduced in cells expressing wild-type p53, whereas cells transformed with mutant p53 genes derived from human tumors were less affected. Coexpression of the normal p53 protein with the human cell cycle-regulated protein kinase CDC2Hs resulted in much more pronounced growth inhibition that for p53 alone. Cells expressing p53 and CDC2Hs were partially arrested in G1, as determined by morphological analysis and flow cytometry. p53 was phosphorylated when expressed in the yeast, but differences in phosphorylation did not explain the growth inhibition attributable to coexpression of p53 and CDC2Hs. These results suggest that wild-type p53 has a growth-inhibitory activity in S. cerevisiae similar to that observed in mammalian cells and suggests that this yeast may provide a useful model for defining the pathways through which p53 acts.

scholarly journals Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity

2018 ◽  
Vol 39 (4) ◽  
Author(s):  
Leixiang Yang ◽  
Tanjing Song ◽  
Qian Cheng ◽  
Lihong Chen ◽  
Jiandong Chen
Keyword(s):  
Tumor Cells ◽  
Recent Work ◽  
Intramolecular Interaction ◽  
E3 Ligase ◽  
Mutant P53 ◽  
Wild Type ◽  
Gain Of Function ◽  
Core Domain ◽  
Acidic Domain ◽  
Wild Type P53

ABSTRACT Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53 and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells.

scholarly journals Crosstalk between p53 and TGF-β Signalling

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Rebecca Elston ◽  
Gareth J. Inman
Keyword(s):  
Transcriptional Activation ◽  
Cancer Biology ◽  
Target Genes ◽  
Tumour Progression ◽  
Signal Transduction Pathway ◽  
Mirna Biogenesis ◽  
Mutant P53 ◽  
Wild Type ◽  
P53 Family ◽  
Wild Type P53

Wild-type p53 and TGF-β are key tumour suppressors which regulate an array of cellular responses. TGF-β signals in part via the Smad signal transduction pathway. Wild-type p53 and Smads physically interact and coordinately induce transcription of a number of key tumour suppressive genes. Conversely mutant p53 generally subverts tumour suppressive TGF-β responses, diminishing transcriptional activation of key TGF-β target genes. Mutant p53 can also interact with Smads and this enables complex formation with the p53 family member p63 and blocks p63-mediated activation of metastasis suppressing genes to promote tumour progression. p53 and Smad function may also overlap during miRNA biogenesis as they can interact with the same components of the Drosha miRNA processing complex to promote maturation of specific subsets of miRNAs. This paper investigates the crosstalk between p53 and TGF-β signalling and the potential roles this plays in cancer biology.

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