Tracing the protectors path from the germ line to the genome

Coutandin, Daniel; Ou, Horng D.; Löhr, Frank; Dötsch, Volker

doi:10.1073/pnas.1001069107

Cited by 11 publications

(15 citation statements)

References 134 publications

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“…16 Drosophila p53 is more similar to human p53 in that it lacks the SAM protein-interaction domain found in the C-terminus of p63 and p73. 7,[34][35][36][37] Orthologs in many invertebrates, including ciliates, contain a SAM domain, suggesting that the p63 paralogs represent an ancestral form. 7,36,37 Each of the orthologs in Molluscs and some Arachnids also encode multiple protein isoforms, suggesting that this property is an ancient attribute of the p53 gene family.…”

Section: Discussionmentioning

confidence: 99%

“…7,[34][35][36][37] Since the initial description of Drosophila p53, most investigations into its function have focused on a single 44 kD protein isoform, but expression of a 56 kD isoform has also been described. 15,34,35,38 The current genome annotation based on deep RNA sequencing predicts four mRNA isoforms (A, B, C, and E) and three proteins, with transcript A and C encoding the same well-characterized 44 kD protein 39,40 ( Figure 1a).…”

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confidence: 99%

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The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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The p53 protein is a major mediator of the cellular response to genotoxic stress and is a crucial suppressor of tumor formation. In a variety of organisms, p53 and its paralogs, p63 and p73, each encode multiple protein isoforms through alternative splicing, promoters, and translation start sites. The function of these isoforms in development and disease are still being defined. Here, we evaluate the apoptotic potential of multiple isoforms of the single p53 gene in the genetic model Drosophila melanogaster. Most previous studies have focused on the p53A isoform, but it has been recently shown that a larger p53B isoform can induce apoptosis when overexpressed. It has remained unclear, however, whether one or both isoforms are required for the apoptotic response to genotoxic stress. We show that p53B is a much more potent inducer of apoptosis than p53A when overexpressed. Overexpression of two newly identified short isoforms perturbed development and inhibited the apoptotic response to ionizing radiation. Analysis of physiological protein expression indicated that p53A is the most abundant isoform, and that both p53A and p53B can form a complex and co-localize to sub-nuclear compartments. In contrast to the overexpression results, new isoformspecific loss-of-function mutants indicated that it is the shorter p53A isoform, not full-length p53B, that is the primary mediator of pro-apoptotic gene transcription and apoptosis after ionizing radiation. Together, our data show that it is the shorter p53A isoform that mediates the apoptotic response to DNA damage, and further suggest that p53B and shorter isoforms have specialized functions.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

The function of Drosophila p53 isoforms in apoptosis

et al. 2015

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“…12,13 In the starlet sea anemone, UV-induced germ cell death requires the function of the p53 ortholog nvp63.…”

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Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network

Cordeiro²,

et al. 2013

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Non-proliferating oocytes within avascular regions of the ovary are exquisitely susceptible to chemotherapy. Early menopause and sterility are unintended consequences of chemotherapy, and efforts to understand the oocyte apoptotic pathway may provide new targets for mitigating this outcome. Recently, the c-Abl kinase inhibitor imatinib mesylate (imatinib) has become the focus of research as a fertoprotective drug against cisplatin. However, the mechanism by which imatinib protects oocytes is not fully understood, and reports of the drug's efficacy have been contradictory. Using in vitro culture and subrenal grafting of mouse ovaries, we demonstrated that imatinib inhibits the cisplatin-induced apoptosis of oocytes within primordial follicles. We found that, before apoptosis, cisplatin induces c-Abl and TAp73 expression in the oocyte. Oocytes undergoing apoptosis showed downregulation of TAp63 and upregulation of Bax. While imatinib was unable to block cisplatin-induced DNA damage and damage response, such as the upregulation of p53, imatinib inhibited the cisplatin-induced nuclear accumulation of c-Abl/TAp73 and the subsequent downregulation of TAp63 and upregulation of Bax, thereby abrogating oocyte cell death. Surprisingly, the conditional deletion of Trp63, but not DNp63, in oocytes inhibited apoptosis, as well as the accumulation of c-Abl and TAp73 caused by cisplatin. These data suggest that TAp63 is the master regulator of cisplatin-induced oocyte death. The expression kinetics of TAp63, c-Abl and TAp73 suggest that cisplatin activates TAp63-dependent expression of c-Abl and TAp73 and, in turn, the activation of TAp73 by c-Abl-induced BAX expression. Our findings indicate that imatinib protects oocytes from cisplatin-induced cell death by inhibiting c-Abl kinase, which would otherwise activate TAp73-BAX-mediated apoptosis. Thus, imatinib and other c-Abl kinase inhibitors provide an intriguing new way to halt cisplatin-induced oocyte death in early follicles and perhaps conserve the endocrine function of the ovary against chemotherapy.

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“…Detailed functional and structural investigations of p63 and p73, two homologs of the tumor suppressor protein p53, have suggested that p63 is the most ancient member of this protein family, from which the other members have evolved. [1][2][3] This idea was particularly fueled by the discovery that invertebrates like Caenorhabditis elegans have p53-like proteins [4][5][6] that are more closely related to p63 than to p53. [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.…”

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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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Tracing the protectors path from the germ line to the genome

Cited by 11 publications

References 134 publications

The function of Drosophila p53 isoforms in apoptosis

The function of Drosophila p53 isoforms in apoptosis

Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network

Analysis of the oligomeric state and transactivation potential of TAp73α

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