DNA repair is activated in early stages of p53-induced apoptosis

Geske, F. Jon; Nelson, AA; Lieberman, R.; Strange, Robert; Sun, Te-Ping; Gerschenson, L. E.

doi:10.1038/sj.cdd.4400663

Cited by 56 publications

(56 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…28 -30 It has been suggested that p53 play a role in regulating NER, especially the GGR subpathway. [31][32][33][34][35][36] As shown in our experiment, a heterozygous loss of p53 appears to act synergistically to a NER defect in tongue tumor induction. The bulky DNA lesions elicited by 4NQO are known to substrate for GGR and 4NQO-DNA damage per se provokes up-regulation of p53.…”

Section: Discussionmentioning

confidence: 82%

p53 Haploinsufficiency Profoundly Accelerates the Onset of Tongue Tumors in Mice Lacking the Xeroderma Pigmentosum Group A Gene

Ide

Kitada

Sakashita

et al. 2003

The American Journal of Pathology

View full text Add to dashboard Cite

Mice lacking the xeroderma pigmentosum group A gene (XPA؊/؊ mice), which have a complete deficiency in nucleotide excision repair (NER), are highly predisposed to tongue squamous cell carcinoma (SCC) when exposed to 4-nitroquinoline 1-oxide (4NQO). To explore the effects of the interaction of the NER machinery with p53 in oral tumorigenesis, we generated an XPA؊/؊ mouse strain carrying mutant alleles for p53. This mouse model of 4NQO carcinogenesis demonstrated that despite the same tumor frequency, XPA؊/؊p53؉/؊ mice reached 100% SCC incidence at 25 weeks compared with 50 weeks for XPA؊/؊p53؉/؉ littermates. XPA؊/؊p53؊/؊ mice succumbed to spontaneous thymic lymphomas before the development of tongue tumors (before 13 weeks of age). SCC originated in XPA؊/؊p53؉/؊ mice maintained the p53؉/؊ genotype and the retained wild-type p53 allele appeared to be structurally intact. Only one of 20 XPA؊/؊p53؉/؉ SCC showed a missense mutation of p53. Collectively, the accelerated tongue tumor growth may be a consequence of haploinsufficiency but not of mutation of p53 in the context of NER deficiency. p53 plays a complex and critical role in cellular proofreading in response to many stress signals including potentially oncogenic DNA damage.

show abstract

Section: Discussionmentioning

confidence: 82%

p53 Haploinsufficiency Profoundly Accelerates the Onset of Tongue Tumors in Mice Lacking the Xeroderma Pigmentosum Group A Gene

Ide

Kitada

Sakashita

et al. 2003

The American Journal of Pathology

View full text Add to dashboard Cite

show abstract

“…Initial results from our laboratory have shown that DNA repair is activated early in p53-induced apoptosis, and that early stages may indeed be reversible. 32 This current work follows up on these initial findings and provides more evidence that early stages of p53-induced apoptosis are reversible. Using a temperaturesensitive p53 cell line (p53ts), we show that p53 induces PS-flipping in these cells.…”

Section: Introductionmentioning

confidence: 99%

“…32 To substantiate these results, we have further analyzed p53-induced apoptosis and its reversibility. We have used a temperature-sensitive p53 cell line (p53ts) in which p53 in inactive at 378C.…”

Section: Ps Is Externalized By P53 Activationmentioning

confidence: 99%

Early stages of p53-induced apoptosis are reversible

et al. 2001

Self Cite

View full text Add to dashboard Cite

Apoptosis is a type of physiological cell death that occurs during development, normal tissue homeostasis, or as a result of different cellular insults. The phenotype of an apoptotic cell isrelativelyconsistentinmostcasesofapoptosisandinvolves at least changes in the cell membrane, proteolysis of cytoplasmic and nuclear proteins, and eventual destruction of nuclear DNA. Our laboratory is interested in the reversibility of apoptosis. We have initial evidence that DNA repair is activated early in p53-induced apoptosis and may be involved in its reversibility. The present work further strengthens our proposition that p53-inducedapoptosisisreversible. We show that p53 activation induces phosphatidylserine (PS) externalization early in apoptosis, and that these early apoptotic cells with externalized PS can be rescued and proliferate if the apoptotic stimulus is removed. In addition, we show that unscheduled DNA synthesis occurs in early apoptotic cells, and that if DNA repair is inhibited by aphidicolin, apoptosis is accelerated. These results confirm that early p53-induced apoptotic cells can be rescued from the apoptotic program, and that DNA repair can modulate that cell death process.Cell Death and Differentiation (2001) 8, 182 ± 191.

show abstract

“…Early stages of apoptosis may be reversible, as shown by Geske et al, [2000] possibly due to the activation of DNA repair. However, the disruption of the MMP is regarded to be an early, albeit already irreversible stage of apoptosis.…”

Section: Only Early Removal Of Mtbitc Saves the Cells From Apoptosismentioning

confidence: 99%

MTBITC mediates cell cycle arrest and apoptosis induction in human HepG2 cells despite its rapid degradation kinetics in the in vitro model

Lamy

Mersch-Sundermann

2009

Environ and Mol Mutagen

View full text Add to dashboard Cite

Despite the great variety of structure homologous, experimental research on the cancer preventive properties of isothiocyanates (ITCs) is limited to only a fractional amount thereof so far. Especially the degradation of these compounds in the experimental system has not been investigated so far. In this study, we investigated the effect of 4-methylthiobutyl isothiocyante (MTBITC) on the proliferation of human hepatoma (HepG2) cells and underlying mechanisms. A concentration and time-dependent reduction in proliferation activity could be observed in cells treated with MTBITC exceeding 10 lM. At these concentrations MTBITCinduced apoptosis in HepG2 cells could be observed by internucleosomal DNA fragmentation, flow cytometry analysis, and the detection of single-stranded apoptotic DNA. In all the three assays, clear apoptotic events were present after 6-hr exposure to MTBITC. Apoptosis induction was accompanied by a time-dependent arrest of HepG2 cells at the G2/M phase of the cell cycle. This study shows for the first time the inhibitory potency of MTBITC on metabolically competent hepatoma cells, whereas the loss of reduced glutathione and its impact on mitochondria seem to be the major processes involved in the initiation and execution of the apoptotic cell death. The results of this study also showed that irrespective of the intense degradation kinetics of MTBITC, the strong cytostatic effect of the ITC was not markedly affected by it and suggests that although ITCs are only present at maximum concentrations in a living system for a rather short time, this might be sufficient to exert their therapeutic effects. Environ. Mol. Mutagen. 50:190-200, 2009. V V C 2009 Wiley-Liss, Inc.

show abstract

DNA repair is activated in early stages of p53-induced apoptosis

Cited by 56 publications

References 51 publications

p53 Haploinsufficiency Profoundly Accelerates the Onset of Tongue Tumors in Mice Lacking the Xeroderma Pigmentosum Group A Gene

p53 Haploinsufficiency Profoundly Accelerates the Onset of Tongue Tumors in Mice Lacking the Xeroderma Pigmentosum Group A Gene

Early stages of p53-induced apoptosis are reversible

MTBITC mediates cell cycle arrest and apoptosis induction in human HepG2 cells despite its rapid degradation kinetics in the in vitro model

Contact Info

Product

Resources

About