Regulation of the cell cycle by p53 after DNA damage in an amphibian cell line

Bensaad, Karim; Rouillard, Dany; Soussi, Thierry

doi:10.1038/sj.onc.1204492

Cited by 12 publications

(12 citation statements)

References 36 publications

(36 reference statements)

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“…An explanation for such a requirement may be found in the role of p53 in the maintenance of genome integrity, which we have shown are conserved in salamanders, as has previously been shown in other amphibians (39). Actively dividing cells within the blastema are likely to encounter replicative challenges that would require the genome-protective activities of p53.…”

Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modmentioning

confidence: 72%

Regulation of p53 is critical for vertebrate limb regeneration

Yun

Gates

Brockes

2013

Proc. Natl. Acad. Sci. U.S.A.

103

101

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Extensive regeneration of the vertebrate body plan is found in salamander and fish species. In these organisms, regeneration takes place through reprogramming of differentiated cells, proliferation, and subsequent redifferentiation of adult tissues. Such plasticity is rarely found in adult mammalian tissues, and this has been proposed as the basis of their inability to regenerate complex structures. Despite their importance, the mechanisms underlying the regulation of the differentiated state during regeneration remain unclear. Here, we analyzed the role of the tumor-suppressor p53 during salamander limb regeneration. The activity of p53 initially decreases and then returns to baseline. Its down-regulation is required for formation of the blastema, and its upregulation is necessary for the redifferentiation phase. Importantly, we show that a decrease in the level of p53 activity is critical for cell cycle reentry of postmitotic, differentiated cells, whereas an increase is required for muscle differentiation. In addition, we have uncovered a potential mechanism for the regulation of p53 during limb regeneration, based on its competitive inhibition by ΔNp73. Our results suggest that the regulation of p53 activity is a pivotal mechanism that controls the plasticity of the differentiated state during regeneration. myogenesis | chondrogenesis | p73 | carcinogenesis U nlike mammals, which exhibit limited regenerative abilities, the urodele amphibians-or salamanders-are capable of regenerating an extraordinary range of body structures, including ocular tissues, tail, sections of the heart, parts of the nervous system, and entire limbs (1). In salamanders, such as the newt and axolotl, limb regeneration depends on the formation of a blastema, a mound of progenitor cells of restricted potential that arises after amputation (2-4). Following a period of proliferation, blastema cells redifferentiate and restore the structures of the limb.Extensive evidence indicates that limb regeneration depends on reprogramming of cells in mature limb tissues. Upon amputation, muscle, cartilage, and connective tissue cells underneath the injury site lose their differentiated characteristics and reenter the cell cycle to give rise to the blastema (5-8). This mechanism has also been observed during zebrafish heart and fin regeneration (9, 10). In contrast, reversals of the differentiated state are rarely observed in mammalian tissues, which led to the suggestion that inability to undergo dedifferentiation could contribute to the failure of regeneration in mammals (11). Despite their significance, the mechanisms underlying regulation of the differentiated state during vertebrate regeneration remain poorly understood.Recently, the tumor suppressor p53, whose best-characterized functions are in the maintenance of genome stability (12), has been implicated in the suppression of artificial cell reprogramming to pluripotency (13-17) and the promotion of differentiation pathways in mammals (18). In addition, it has been observed that inhibiting p...

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Section: Salamander δNp73 Acts As a P53 Dominant-negative And Its Modmentioning

confidence: 72%

Regulation of p53 is critical for vertebrate limb regeneration

Yun

Gates

Brockes

2013

Proc. Natl. Acad. Sci. U.S.A.

103

101

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“…The cells were resuspended in PBS and fixed with ethanol (75%). BrdUrd-labeled cells were detected as described by Bensaad et al (26). Briefly, the nuclei were isolated following treatment with pepsin 0.5% in 30 mM HCl for 20 min, and cellular DNA was partially denatured with 2 N HCl for 20 min at 37°C.…”

Section: Figmentioning

confidence: 99%

Ionizing Radiation Triggers Chromatin-bound kin17 Complex Formation in Human Cells

Biard¹,

Miccoli²,

Despras³

et al. 2002

Journal of Biological Chemistry

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The human DNA-binding HSA kin17 protein cross-reacts with antibodies raised against the stress-activated Escherichia coli RecA protein. We show here that HSA kin17 protein is directly associated with chromosomal DNA as judged by cross-linking experiments on living cells. We detected increased amounts of DNAbound HSA kin17 protein 24 h after ␥ irradiation, with 2.6-fold more HSA kin17 molecules after 6 Gy of irradiation (46,000 -117,000 molecules). At this time we observed that highly proliferating RKO cells displayed the concentration and co-localization of HSA kin17 and replication protein A in nucleoplasmic foci. Our results suggest that 24 h post-irradiation HSA kin17 protein may localize at the sites of unrepaired DNA damages. RKO clones expressing an HSA KIN17 antisense transcript (RASK.5 and RASK.13 cells) revealed that reduced HSA kin17 protein levels are correlated with a decrease in clonogenic cell growth and cell proliferation, as well as an accumulation of cells in early and mid-S phase. Taken together our observations support the idea that HSA kin17 protein is a DNA maintenance protein involved in the cellular response to the presence of DNA damage and suggest that it helps to overcome the perturbation of DNA replication produced by unrepaired lesions. Ionizing radiation (IR)1 induces a large range of DNA damage, including DNA double-strand breaks (DSBs), which represent a major threat to the integrity of mammalian genomes through chromosomal breakages and rearrangements (1). In mammalian cells, DSBs are repaired either by the homologous recombinational repair or by nonhomologous end joining (2, 3). DSB repair pathways are usually characterized by the sequestration of many factors into discrete nuclear foci at the sites of DNA lesions and until completion of DSB repair (4). Some of the proteins belonging to these pathways act as a sensor for DNA damage or are involved in cell cycle checkpoints. This is the case for the histone H2AX, 53BP1, RPA, Rad51, BRCA1, or the Mre11-Rad50-Nbs1 nuclease complex (4 -8). For instance, the tumor suppressor gene BRCA1, previously involved in the regulation of the replication checkpoint and transcription-coupled repair, forms a multiprotein complex with Mre11-Rad50-Nbs1 and other proteins following irradiation, termed as BASC (BRCA1-associated surveillance complex), which may serve as a sensor of DNA lesions (8,9).In this cascade of IR-induced proteins forming nuclear foci, we characterized here the HSA kin17 protein. Murine MMU kin17 protein was identified on the basis of a cross-reactivity with antibodies raised against the Escherichia coli RecA protein, a key enzyme in homologous recombination and recombinational repair of damaged DNA (10, 11). This cross-reactivity stemmed from a sequence homology stretching over 39 amino acids highly conserved during evolution (12). This domain is located in the carboxyl-terminal region of the E. coli RecA protein, a region involved in the regulation of DNA binding (13). Recent data show that kin17 proteins are highly conserved d...

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“…The finding that DNA damage can induce growth arrest in frog cells suggests that either another CDKI could be the target of p53 or that an alternative mechanism is involved (Bensaad et al, 2001). This observation together with the fact that the fly and the C. elegans ancestor of the p53 family are devoid of any growth arrest activity despite apoptotic activity suggest that the cell cycle arrest function of p53 is recent.…”

Section: Other P53 Target Genesmentioning

confidence: 67%

“…This is the first time that p53 RE has been reported in nonmammalian species. Experimental evidence is necessary to demonstrate the biological activity of these sequences, but several lines of experimental evidence already suggest that mammalian and X. laevis p53 are interchangeable and behave in similar ways (Hardy-Bessard et al, 1998;Bensaad et al, 2001).…”

Section: Other P53 Target Genesmentioning

confidence: 99%

Data mining the p53 pathway in the Fugu genome: evidence for strong conservation of the apoptotic pathway

2003

Self Cite

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The p53 tumour suppressor gene belongs to a small family of related proteins that includes two other members, p63 and p73. Phylogenetic and functional studies suggest that p63 and p73 are ancient genes that have essential roles in normal development, whereas p53 seems to have evolved more recently to prevent cell transformation. In mammalian cells, a plethora of proteins have been found to specifically regulate p53 activity. The genome of the fish Fugu rubripes has been recently published. It is the second vertebrate genome for which the entire sequence is now available. Phylogenetic studies are essential in order to analyse and define signalling pathways important for cell cycle regulation. The presence or absence of a critical member in any pathway can shed light about the evolution of these pathways. The Fugu genome databank has been analysed for several members of the p53 network, including p53, p63 and p73. A good conservation of the network that regulates p53 stability and apoptosis has been found. We also discovered that some cofactors that cooperate with p53 for apoptosis are also well conserved and belong to multigene families not detected in the human genome.

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Regulation of the cell cycle by p53 after DNA damage in an amphibian cell line

Cited by 12 publications

References 36 publications

Regulation of p53 is critical for vertebrate limb regeneration

Regulation of p53 is critical for vertebrate limb regeneration

Ionizing Radiation Triggers Chromatin-bound kin17 Complex Formation in Human Cells

Data mining the p53 pathway in the Fugu genome: evidence for strong conservation of the apoptotic pathway

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