Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network

Derry, W. Brent; Bierings, Ruben; Iersel, Martijn P. van; Satkunendran, Thevagi; Reinke, V; Rothman, Joel H.

doi:10.1038/sj.cdd.4402075

Cited by 61 publications

(72 citation statements)

References 41 publications

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“…27 As indicated by an abundant literature, p53 allows for the adaptation of and response to genotoxic stress 28 in diverse organisms including C. elegans 29 and it has been implicitly speculated that this function would account for the impact of p53 on life-span regulation. Autophagy is considered as a mechanism to cope with metabolic stress and organellar damage.…”

Section: Resultsmentioning

confidence: 99%

The effects of p53 on whole organism longevity are mediated by autophagy

Tavernarakis¹,

Pasparaki²,

Tasdemir³

et al. 2008

Autophagy

129

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The tumor suppressor protein p53 has a major impact on organismal aging. Recently it has become clear that p53 not only controls DNA damage responses, senescence and apoptosis but also plays a major role in the control of autophagy. Thus, deletion, depletion, or inhibition of p53 induces autophagy in human, mouse and nematode cells. We therefore tested the hypothesis that the mutation of the p53 orthologue CEP-1 might increase the life span of Caenorhabditis elegans through an increase in baseline autophagy. For this, we evaluated the survival of nematodes lacking cep-1, alone or in combination with RNA inference with the autophagy gene bec-1 (which encodes the orthologue of Atg6/Beclin 1). cep-1 mutants exhibited a prolonged life span. While BEC-1 depletion during adult life did not cause significant modification of the life expectancy of wild type controls, it did reduce the increased life span of cep-1 mutants down to approximately normal levels. These results indicate that the life span-extending effect of the cep-1 mutation is mediated by autophagy. These results lend support to the hypothesis that autophagy has a broad positive impact on organismal aging.

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Section: Resultsmentioning

confidence: 99%

The effects of p53 on whole organism longevity are mediated by autophagy

Tavernarakis¹,

Pasparaki²,

Tasdemir³

et al. 2008

Autophagy

129

View full text Add to dashboard Cite

show abstract

“…[7][8][9] In C. elegans the Cep-1 protein does not act as a tumor suppressor but is expressed in germ cells where it serves as a quality control factor. 10 This function is also preserved in mammals where p63 is highly expressed in female oocytes. 11 Detection of DNA damage leads to the activation of p63, which results in the elimination of these compromised oocytes.…”

mentioning

confidence: 89%

Analysis of the oligomeric state and transactivation potential of TAp73α

et al. 2013

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The proteins p73 and p63 are members of the p53 protein family and are involved in important developmental processes. Their high sequence identity with the tumor suppressor p53 has suggested that they act as tumor suppressors as well. While p63 has a crucial role in the maintenance of epithelial stem cells and in the quality control of oocytes without a clear role as a tumor suppressor, p73 0 s tumor suppressor activity is well documented. In a recent study we have shown that the transcriptional activity of TAp63a, the isoform responsible for the quality control in oocytes, is regulated by its oligomeric state. The protein forms an inactive, dimeric and compact conformation in resting oocytes, while the detection of DNA damage leads to the formation of an active, tetrameric and open conformation. p73 shows a high sequence identity to p63, including those domains that are crucial in stabilizing its inactive state, thus suggesting that p73's activity might be regulated by its oligomeric state as well. Here, we have investigated the oligomeric state of TAp73a by size exclusion chromatography and detailed domain interaction mapping, and show that in contrast to p63, TAp73a is a constitutive open tetramer. However, its transactivation potential depends on the cellular background and the promoter context. These results imply that the regulation of p73 0 s transcriptional activity might be more closely related to p53 than to p63.

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“…Apoptosis is maximally induced by genotoxic agents that cause DNA double-strand breaks. Increased apoptosis is also observed with agents that primarily act by conferring base modi fi cations such as EMS or ENU, or upon UV treatment that leads to the formation of tyrosine and thymidine dimers (Gartner et al 2000 ;Derry et al 2007 ;Stergiou et al 2007 ) . Similar to physiological cell death, DNA damage-induced apoptosis is restricted to late pachytene stage cells and requires the core apoptotic machinery formed by CED-3 and CED-4 proteins (Gartner et al 2000 ) .…”

Section: Dna Damage Checkpoint Signallingmentioning

confidence: 99%

“…Thus CEP-1 does not appear to have a prominent DNA repair function in response to ionizing irradiation. Interestingly, CEP-1 seems to be required for both UV-induced cell cycle arrest and apoptosis (Derry et al 2007 ;Stergiou et al 2007 ) . Like mammalian p53, CEP-1 is phosphorylated in response to ionizing irradiation but the importance of this has not been identi fi ed (Schumacher et al 2005b ;Gao et al 2008 ) .…”

Section: Pathways Leading To Dna Damage-induced Apoptosismentioning

confidence: 99%

Germ Cell Apoptosis and DNA Damage Responses

Bailly

Gartner

2012

Advances in Experimental Medicine and Biology

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In the past 12 years, since the fi rst description of C. elegans germ cell apoptosis, this area of research rapidly expanded. It became evident that multiple genetic pathways lead to the apoptotic demise of germ cells. We are only beginning to understand how these pathways that all require the CED-9/Bcl-2, Apaf-1/CED-4 and CED-3 caspase core apoptosis components are regulated. Physiological apoptosis, which likely accounts for the elimination of more than 50% of all germ cells, even in unperturbed conditions, is likely to be required to maintain tissue homeostasis. The best-studied pathways lead to DNA damage-induced germ cell apoptosis in response to a variety of genotoxic stimuli. This apoptosis appears to be regulated similar to DNA damage-induced apoptosis in the mouse germ line and converges on p53 family transcription factors. DNA damage response pathways not only lead to apoptosis induction, but also directly affect DNA repair, and a transient cell cycle arrest of mitotic germ cells. Finally, distinct pathways activate germ cell apoptosis in response to defects in meiotic recombination and meiotic chromosome pairing.

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Regulation of developmental rate and germ cell proliferation in Caenorhabditis elegans by the p53 gene network

Cited by 61 publications

References 41 publications

The effects of p53 on whole organism longevity are mediated by autophagy

The effects of p53 on whole organism longevity are mediated by autophagy

Analysis of the oligomeric state and transactivation potential of TAp73α

Germ Cell Apoptosis and DNA Damage Responses

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