<i>Drosophila</i> p53 integrates the antagonism between autophagy and apoptosis in response to stress

Robin, Marion; Issa, Abdul-Raouf; Santos, Cristiana C.; Napoletano, Francesco; Petitgas, Céline; Chatelain, Gilles; Ruby, Mathilde; Walter, Ludivine; Birman, Serge; Domingos, Pedro; Calvi, Brian R.; Mollereau, Bertrand

doi:10.1080/15548627.2018.1558001

Cited by 36 publications

(37 citation statements)

References 69 publications

(99 reference statements)

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“…The p53 B41.5 allele is a 14bp deletion plus 1bp insertion in the unique second coding exon of p53B, removing p53B coding sequence and creating a frameshift with a stop codon soon afterward ( Figure 2B, Figure S3A). We had previously shown that p53A mRNA structure is perturbed and p53A protein is undetectable in homozygous p53 A2.3 animals, whereas p53B mRNA is still expressed ( Figure S3B) (Robin et al 2019). Conversely, RT-PCR indicated that in the p53 B41.5 strain the p53A isoform is still expressed ( Figure S3B).…”

Section: Resultsmentioning

confidence: 85%

“…The resulting p53 A2.3 allele is a 23bp deletion and 7bp insertion within the unique p53A 5' exon ( Figure 2A, Figure S3A). This deletion extends downstream into the first p53A intron removing both p53A coding sequence and first RNA splicing donor site (Figure 2A, Figure S3A) (Robin et al 2019). This coding sequence and splice donor site are shared with p53C mRNA, which is predicted to encode a p53 protein isoform that is identical to that encoded by p53A mRNA ( Figure 1A).…”

Section: Resultsmentioning

confidence: 99%

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Drosophila p53isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control

Chakravarti

Thirimanne

Calvi

2020

Preprint

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Abstractp53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. Using Drosophila as a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B both respond to meiotic DNA breaks and are required during oogenesis to prevent persistent germline DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is required to activate a meiotic pachytene checkpoint. Our findings indicate that Drosophila p53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.

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Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Drosophila p53isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control

Chakravarti

Thirimanne

Calvi

2020

Preprint

Self Cite

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“…The loss of cartilage cells, osteocyte, and osteoblasts is hypothesized to drive SANFH, although the type of cell death is not completely clear. Autophagy is an auto‐catabolic recycling process of eukaryotic cells that is frequently dysregulated in cancer, inflammatory diseases, autoimmune diseases, aging, etc. Our preliminary results show that SANFH is associated with autophagy, and the autophagy‐related Beclin 1 and microtubule‐associated protein 1 light chain 3 (MAP1LC3) are upregulated in osteoblasts.…”

Section: Introductionmentioning

confidence: 75%

Mechanism of Methylprednisolone‐Induced Primary Cilia Formation Disorder and Autophagy in Osteoblasts

Zhao

Liu

Guo

et al. 2020

Orthopaedic Surgery

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Objective: To study the role of primary cilia formation disorder and osteoblasts autophagy in the pathogenesis of steroid-induced avascular necrosis of the femoral head (SANFH).Methods: Osteoblasts were isolated from rabbit bones and treated with 1 μM Methylprednisolone for 0, 12, 24, 48, and 72 h. The Beclin1, MAP1LC3, Atg-5, Atg-12, IFT20 and OFD1 mRNAs and proteins were detected by PCR and Western blotting, and their correlation was statistically analyzed. The lengths of osteoblast cilia were measured under a laser confocal microscope, and the autophagy flux was tracked by transfecting the osteoblasts with GFP-RFP-LC3 lentivirus.Results: Methylprednisolone significantly upregulated Beclin1, MAP1LC3, Atg-5, Atg-12 and OFD1 mRNAs and proteins in a time-dependent manner, and decreased that of IFT20 (P < 0.05). In addition, the autophagy flux in the osteoblasts also increased and the ciliary length decreased in a time-dependent manner after Methylprednisolone treatment. The length of the cilia were 5.46 AE 0.11 um at 0 h, 4.08 AE 0.09 um at 12 h, 3.07 AE 0.07 um at 24 h, 2.31 AE 0.10 um at 48 h, and finally 1.15 AE 0.04 um at 72 h. Methylprednisolone treatment also affects primary cilium numbers in cultures, for 0 to 72 h. The autophagy regulatory genes, Beclin1, MAP1LC3, Atg-5 and Atg-12, were found to be negatively correlated with IFT20, with an average correlation coefficient of −0.81. A negative correlation was also found between OFD1 and IFT20, with an average correlation coefficient of −0.53. Conclusion:Methylprednisolone inhibits primary cilia formation and promotes autophagy, which could be the pathological basis of SANFH. The exact regulatory mechanism needs to be further studied in vivo.

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“…Expression of Drosophila p53A in photoreceptors has been reported to impair autophagic flux 44 . As p53A contributes specifically to the nuclear enlargement defect and TER94 K2A causes age-dependent Atg8a and p62 accumulation ( Fig.…”

Section: Ter94 K2a Nuclear Expansion Is Associated With P53-mediated mentioning

confidence: 99%

“…Previous studies have suggested that p53A is required for DNA damage-induced apoptosis in dividing cells by activating proapoptotic genes40 , and this isoform also showed a tumor-suppressor function by inducing apoptosis and necrosis during spermatogenesis54 . A recent report suggests that Drosophila p53A and p53B have opposing effect on autophagy and apoptosis, and it is the balance between these p53 isoforms that mediate this cellular life-and-death decision under duress44 . Our observation that p53A is selectively required for this context suggests that deregulated DDR, caused by either TER94 dysfunction or Mu2 accumulation, tips the balance to favor p53A-dependent response.…”

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confidence: 99%

VCP functions to maintain nuclear size by managing DNA damage-induced MDC1–p53–autophagy axis

Chang

Peng

Shih

et al. 2020

Preprint

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Anomalies in nuclear morphology have been linked to aging-related diseases and malignant transformation, although the mechanism responsible for this connection remains unclear. By expressing dominant-negative TER94 (TER94K2A) mutants in Drosophila photoreceptors, we show disruption of VCP (valosin-containing protein, TER94 ortholog in human), an AAA (ATPase associated with various cellular activities) ATPase essential for ubiquitin-dependent segregation or degradation of proteins, causes an age-dependent nuclear size increase. Loss of VCP function leads to accumulations of MDC1 (mediator of DNA damage checkpoint protein 1), a key DNA damage response gene, and increased γH2AV (an indicator of DNA damage), linking excessive DNA damages and associated responses to this enlarged nuclei defect. Indeed, MDC1-overexpression, similar to TER94K2A, increases γH2AV staining and nuclear size. Moreover, TER94 negatively influences MDC1 level and could interact with MDC1, suggesting that MDC1 is a VCP substrate. MDC1 accumulation increases p53 stability, and this VCP-MDC1-p53 connection is functional, as removal of p53 function suppresses the ability of TER94K2A and MDC1 overexpression to increase nuclear size. While p53 is capable of generating multiple isoforms, our genetic evidence suggests that the p53A isoform specifically contributes to this TER94K2A-associated nuclear size increase. Combining our results with a previous report that p53A expression disrupts autophagic flux, we propose that the failure of removing MDC1 in TER94K2A-expressing cells stabilizes p53A, which blocks autophagy and likely hinders the removal of nuclear content, resulting in aberrant nuclear size increase.

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Drosophila p53 integrates the antagonism between autophagy and apoptosis in response to stress

Cited by 36 publications

References 69 publications

Drosophila p53isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control

Drosophila p53isoforms have overlapping and distinct functions in germline genome integrity and oocyte quality control

Mechanism of Methylprednisolone‐Induced Primary Cilia Formation Disorder and Autophagy in Osteoblasts

VCP functions to maintain nuclear size by managing DNA damage-induced MDC1–p53–autophagy axis

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