Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Drosophila Endocycling Cells
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{"title"=>"Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in Drosophila Endocycling Cells", "type"=>"journal", "authors"=>[{"first_name"=>"Bingqing", "last_name"=>"Zhang", "scopus_author_id"=>"55968295300"}, {"first_name"=>"Sonam", "last_name"=>"Mehrotra", "scopus_author_id"=>"15073855500"}, {"first_name"=>"Wei Lun", "last_name"=>"Ng", "scopus_author_id"=>"56375269600"}, {"first_name"=>"Brian R.", "last_name"=>"Calvi", "scopus_author_id"=>"6603174353"}], "year"=>2014, "source"=>"PLoS Genetics", "identifiers"=>{"sgr"=>"84907588692", "doi"=>"10.1371/journal.pgen.1004581", "issn"=>"15537404", "pui"=>"600082976", "isbn"=>"1553-7404 (Electronic) 1553-7390 (Linking)", "pmid"=>"25211335", "scopus"=>"2-s2.0-84907588692"}, "id"=>"69737ba6-7c07-3221-ac5f-a51cba273c82", "abstract"=>"Apoptotic cell death is an important response to genotoxic stress that prevents oncogenesis. It is known that tissues can differ in their apoptotic response, but molecular mechanisms are little understood. Here, we show that Drosophila polyploid endocycling cells (G/S cycle) repress the apoptotic response to DNA damage through at least two mechanisms. First, the expression of all the Drosophila p53 protein isoforms is strongly repressed at a post-transcriptional step. Second, p53-regulated pro-apoptotic genes are epigenetically silenced in endocycling cells, preventing activation of a paused RNA Pol II by p53-dependent or p53-independent pathways. Over-expression of the p53A isoform did not activate this paused RNA Pol II complex in endocycling cells, but over-expression of the p53B isoform with a longer transactivation domain did, suggesting that dampened p53B protein levels are crucial for apoptotic repression. We also find that the p53A protein isoform is ubiquitinated and degraded by the proteasome in endocycling cells. In mitotic cycling cells, p53A was the only isoform expressed to detectable levels, and its mRNA and protein levels increased after irradiation, but there was no evidence for an increase in protein stability. However, our data suggest that p53A protein stability is regulated in unirradiated cells, which likely ensures that apoptosis does not occur in the absence of stress. Without irradiation, both p53A protein and a paused RNA pol II were pre-bound to the promoters of pro-apoptotic genes, preparing mitotic cycling cells for a rapid apoptotic response to genotoxic stress. Together, our results define molecular mechanisms by which different cells in development modulate their apoptotic response, with broader significance for the survival of normal and cancer polyploid cells in mammals.", "link"=>"http://www.mendeley.com/research/low-levels-p53-protein-chromatin-silencing-p53-target-genes-repress-apoptosis-drosophila-endocycling", "reader_count"=>35, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>8, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>2, "Student > Doctoral Student"=>1, "Researcher"=>8, "Student > Ph. D. Student"=>15, "Student > Postgraduate"=>2, "Student > Master"=>2, "Other"=>1, "Student > Bachelor"=>3, "Professor"=>1}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>8, "Agricultural and Biological Sciences"=>24}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>24}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>8}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>0}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1672362"], "description"=>"<p>(A–D) Expression of the <i>hid-GFP</i> promoter-reporter in 3<sup>rd</sup> instar, mitotic cycling eye-antennal discs (A,B) or endocycling salivary glands (C,D) without (A,C) or with (B,D) 4,000 rads of IR (Scale bars are 100 microns). Other mitotic cycling tissues, e.g. larval brain and wing/leg imaginal discs, showed similar GFP expression patterns. (E–H) ChIP-qPCR of 3<sup>rd</sup> instar larval brain and imaginal disc (B–D, light gray) and salivary gland (SG, dark gray ) indicates that the <i>rpr</i> and <i>hid</i> genes are enriched for the silencing chromatin marks H3K27Me3 (E,F) and H3K9Me3 (G), and have a deficit of the activating mark poly AcH4 (H) in endocycling cells. X-axis: primer position relative to TSS with p53RE in red. Control loci: Act5C, active in both tissue types; Ubx; silenced in SG; heterochromatic locus H23, silenced in B–D and SG. Y-axis is qPCR of pellet DNA normalized to input and either Ubx (E,F), H23 (G), or Act5C (H) levels in B–D. Error bars represent the range of data from two (F–H) or three (E) independent ChIP experiments.</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167770, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.g001", "stats"=>{"downloads"=>0, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Pro_apoptotic_genes_at_the_H99_locus_are_transcriptionally_silent_and_have_repressive_chromatin_marks_in_endocycling_cells_/1167770", "title"=>"Pro-apoptotic genes at the H99 locus are transcriptionally silent and have repressive chromatin marks in endocycling cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672457"], "description"=>"<p>(A) RT-qPCR quantification of p53 isoform and total mRNA expression levels in different tissue types. Levels were normalized to total mRNA in B–D, which was defined as 1. Error bars represent S.E.M. from three independent experiments. (B) Strategy for tagging p53 BAC with mCherry (p53-Ch) on the common C terminus of all isoforms. (C–D) p53-Ch binds to p53REs in <i>rpr</i> (C) and <i>hid</i> (D) promoter-enhancer in mitotic but not endocycling tissues. ChIP-qPCR analysis using anti-DsRed antibody on 3<sup>rd</sup> instar B–D (▪) and SG (•) cells from the <i>p53-Ch; p53<sup>5A-1-4</sup></i> fly strain. The control strain expresses only DsRed (▴). X-axis: primer position relative to TSS with p53RE in red. Y axis: qPCR value with the −6,000 in <i>rpr</i> and the −4,000 in <i>hid</i> defined as 1. Error bars represent the range of data from two independent biological repeats. (E–F′) p53-Ch fluorescence and DAPI labeling of mitotic cycling cells of 3<sup>rd</sup> instar larval antenna disc (E,E′) and salivary glands (SG) (F, F′). Scale bars are 10 microns in panels and higher magnification insets. (G) Western blot with anti-p53 to detect endogenous p53 in mitotic cycling larval Brain and Disc (B–D, lanes 1–4), endocycling salivary gland (SG, lanes 5,6) or endocycling fat body (FB, lanes 7,8). The B–D extract in lane 2 was diluted 1∶2. The two lanes for each tissue represent biological replicates with equal amounts of total protein determined by Bradford assay and Ponceau S staining (below). (H) Western blot for endogenous p53 protein from 3<sup>rd</sup> instar B–D and SG with normal or compromised proteasome function. The temperature-sensitive dominant negative proteasome subunit transgenes (<i>UAS-pros26<sup>1</sup>; UAS-prosβ2<sup>1</sup></i>) were expressed only in the salivary gland using the <i>Fkh:GAL4</i> driver. 25°C: permissive temperature for proteasome function. 29°C non-permissive temperature. Equal amounts of total protein were loaded as determined by Bradford assay and Ponceau S staining (below), and blotting for alpha-Tubulin is shown for comparison within the same tissue type. (I,J) p53-Ch foci were not detected in SG cells at permissive temperature for proteasome function (I) but were evident in some SG cells at non-permissive temperature (J arrow). The morphology of some SG nuclei was also aberrant when proteasome function was inhibited (J). (K) p53-Ch protein is ubiquitinated in salivary glands. p53-Ch BAC expression in larvae with the dominant negative proteasome transgenes at permissive (lanes 1,3) or non-permissive (2,4) temperature for proteasome function. Lane 1,2 immunoprecipitation with anti-RFP nanobody, Lane 3,4 immunoprecipitation with anti-ubiquitin antibody, followed by Western blotting with anti-p53. Arrows indicate multiple ubiquitinated p53 species whose abundance increase when proteasome function is compromised.</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167848, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.g005", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Proteasome_dependent_p53_protein_degradation_in_endocycling_cells_/1167848", "title"=>"Proteasome-dependent p53 protein degradation in endocycling cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672413"], "description"=>"<p>Expression of the <i>rpr-11-lacZ</i> (A,B) or <i>hid-GFP</i> reporters (C,D) in 3<sup>rd</sup> instar salivary glands over-expressing either <i>UAS:6xMyc:p53A</i> (A,C) or <i>UAS:6xMyc:p53B</i> (B,D) six hours after a 30 min heat pulse with <i>hsp70:GAL4</i>. SG: salivary gland; FB: fat body. Scale bars are 100 microns. (E) RT-qPCR quantification of endogenous <i>rpr</i> and <i>hid</i> mRNA in 3<sup>rd</sup> instar larval salivary gland (SG) cells after over-expression of the indicated transgene or control. Expression was normalized to Act5C, and the level of <i>rpr</i> and <i>hid</i> in controls was defined as 1. Error bars represent S.E.M. for N = 3. (* p≤0.05, *** p≤0.001).</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167810, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.g003", "stats"=>{"downloads"=>0, "page_views"=>24, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_p53B_over_expression_is_a_potent_inducer_of_H99_gene_transcription_/1167810", "title"=>"p53B over-expression is a potent inducer of H99 gene transcription.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672425"], "description"=>"<p>(A, B) Over-expressed p53A or p53B binds to p53REs in <i>hid</i> promoter-enhancer in both B–D (A) and SG (B) tissues. ChIP-qPCR analysis with anti-Myc antibody on 3<sup>rd</sup> instar B–D and SG cells over-expressing <i>UAS:6xMyc:p53A</i> (▪), or <i>UAS:6xMyc:p53B</i> (•) six hours after a 30 min heat induction with <i>hsp70:GAL4</i>, or in controls (▴). X axis: position of the primers relative to the TSS with p53RE in red. Y axis: qPCR value with the −4,000 in <i>hid</i> defined as 1. Error bars represent the range of data from two independent biological repeats. (C,D) ChIP-qPCR analysis using anti-poly AcH4 antibody on 3<sup>rd</sup> instar B–D (C) or SG (D) cells over-expressing either <i>UAS:6xMyc:p53A</i> (▪) or <i>UAS:6xMyc: p53B</i> (•),six hours after a 30 min heat pulse with <i>hsp70:GAL4</i>, or control (▴). X-axis: primer position relative to TSS with p53RE in red. Y axis: qPCR value with the −212 in <i>hid</i> defined as 1. Error bars represent the range of two biological replicates. (E, F) A paused RNA Pol II at the hid gene in unchallenged B–D (E) and SG (F) cells. ChIP-qPCR analysis using anti-phosphorylated Pol II Ser5 in 3<sup>rd</sup> instar B–D and SG cells. X-axis: primer position relative to TSS. Y axis: qPCR values with the +13341 in <i>hid</i> defined as 1. (G) p53B is better than p53A for promoting RNA Pol II elongation. ChIP qPCR for elongating RNA Pol II phoshorylated on Serine 2 (Ser 2) at the hid gene in SG cells over-expressing <i>UAS:6xMyc:p53A</i> (▪), or <i>UAS:6xMyc:p53B</i> (•) six hours after a 30 min heat induction with <i>hsp70:GAL4.</i> X-axis: primer position relative to TSS, Y axis: qPCR values with −6810 in <i>hid</i> defined as 1. See <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004581#pgen.1004581.s006\" target=\"_blank\">Figure S6</a> for similar results at the <i>rpr</i> gene.</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167822, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.g004", "stats"=>{"downloads"=>0, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Both_over_expressed_p53A_and_p53B_bind_and_recruit_acetylation_to_the_hid_gene_but_p53B_is_better_at_activating_elongation_of_a_paused_RNA_Pol_II_/1167822", "title"=>"Both over-expressed p53A and p53B bind and recruit acetylation to the <i>hid</i> gene, but p53B is better at activating elongation of a paused RNA Pol II.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672526", "https://ndownloader.figshare.com/files/1672527", "https://ndownloader.figshare.com/files/1672528", "https://ndownloader.figshare.com/files/1672529", "https://ndownloader.figshare.com/files/1672530", "https://ndownloader.figshare.com/files/1672531", "https://ndownloader.figshare.com/files/1672532", "https://ndownloader.figshare.com/files/1672534", "https://ndownloader.figshare.com/files/1672535"], "description"=>"<div><p>Apoptotic cell death is an important response to genotoxic stress that prevents oncogenesis. It is known that tissues can differ in their apoptotic response, but molecular mechanisms are little understood. Here, we show that <i>Drosophila</i> polyploid endocycling cells (G/S cycle) repress the apoptotic response to DNA damage through at least two mechanisms. First, the expression of all the <i>Drosophila</i> p53 protein isoforms is strongly repressed at a post-transcriptional step. Second, p53-regulated pro-apoptotic genes are epigenetically silenced in endocycling cells, preventing activation of a paused RNA Pol II by p53-dependent or p53-independent pathways. Over-expression of the p53A isoform did not activate this paused RNA Pol II complex in endocycling cells, but over-expression of the p53B isoform with a longer transactivation domain did, suggesting that dampened p53B protein levels are crucial for apoptotic repression. We also find that the p53A protein isoform is ubiquitinated and degraded by the proteasome in endocycling cells. In mitotic cycling cells, p53A was the only isoform expressed to detectable levels, and its mRNA and protein levels increased after irradiation, but there was no evidence for an increase in protein stability. However, our data suggest that p53A protein stability is regulated in unirradiated cells, which likely ensures that apoptosis does not occur in the absence of stress. Without irradiation, both p53A protein and a paused RNA pol II were pre-bound to the promoters of pro-apoptotic genes, preparing mitotic cycling cells for a rapid apoptotic response to genotoxic stress. Together, our results define molecular mechanisms by which different cells in development modulate their apoptotic response, with broader significance for the survival of normal and cancer polyploid cells in mammals.</p></div>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167906, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>["https://dx.doi.org/10.1371/journal.pgen.1004581.s001", "https://dx.doi.org/10.1371/journal.pgen.1004581.s002", "https://dx.doi.org/10.1371/journal.pgen.1004581.s003", "https://dx.doi.org/10.1371/journal.pgen.1004581.s004", "https://dx.doi.org/10.1371/journal.pgen.1004581.s005", "https://dx.doi.org/10.1371/journal.pgen.1004581.s006", "https://dx.doi.org/10.1371/journal.pgen.1004581.s007", "https://dx.doi.org/10.1371/journal.pgen.1004581.s008", "https://dx.doi.org/10.1371/journal.pgen.1004581.s009"], "stats"=>{"downloads"=>33, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/Low_Levels_of_p53_Protein_and_Chromatin_Silencing_of_p53_Target_Genes_Repress_Apoptosis_in_Drosophila_Endocycling_Cells/1167906", "title"=>"Low Levels of p53 Protein and Chromatin Silencing of p53 Target Genes Repress Apoptosis in <i>Drosophila</i> Endocycling Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672472"], "description"=>"<p>In mitotic cycling cells, genotoxic stress activates ATM kinase to phosphorylate Chk2, which in turn phosphorylates p53, resulting in transcriptional activation of the H99 genes. Our data suggest that p53 protein stability in these cells is regulated and tunes a threshold level of p53A protein that induces apoptosis only in response to stress. In addition, our data indicate that p53A protein and a paused RNA Pol II are bound to the H99 promoters in the absence of stress. Preloading of p53A and RNA Pol II may prepare these promoters for a rapid stress response. At later time points, p53-independent pathways also mediate cell death through transcriptional activation of H99 genes. In the endocycling cells, ATM kinase is activated, but p53 protein levels are low, p53A is targeted for degradation by the proteasome, and the promoter-enhancer regions of the H99 genes are epigenetically silenced, further blocking their activation by p53-dependent as well as p53-independent cell death pathways. Together, these mechanisms enforce a tight repression of the apoptotic response to genotoxic stress in endocycling cells.</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167863, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.g007", "stats"=>{"downloads"=>0, "page_views"=>31, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Model_for_tissue_specific_apoptotic_responses_in_Drosophila_/1167863", "title"=>"Model for tissue-specific apoptotic responses in <i>Drosophila</i>.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672473"], "description"=>"1<p>: UAS:RNAi knockdown phenotype of salivary gland in strain with <i>UAS:6xMyc:p53; Fkh:GAL4,UAS:GFP.</i></p><p>Genes recovered in an RNAi screen for salivary gland cell death.</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167864, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.t001", "stats"=>{"downloads"=>6, "page_views"=>16, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genes_recovered_in_an_RNAi_screen_for_salivary_gland_cell_death_/1167864", "title"=>"Genes recovered in an RNAi screen for salivary gland cell death.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672398"], "description"=>"<p>(A) Left panel shows a map of the four predicted RNA transcripts for the <i>Drosophila</i> p53 gene based on cDNA and RNA-seq data annotated in Flybase. Exons are boxes, with predicted ORFs in orange, and 5′ or 3′ UTRs in gray. The right panel shows predicted protein isoform structures and sizes, with transactivation (TA) and DNA binding domains indicated by red and black boxes respectively. The protein domain predictions are adapted from Khoury and Bourdon (2010), which was based on protein alignment and needed further experimental confirmation <a href=\"http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004581#pgen.1004581-Khoury1\" target=\"_blank\">[99]</a>. (B–I) Activated Caspase-3 labeling in 3<sup>rd</sup> instar larval wing discs (B–E) or salivary glands (F–I) after over-expression of <i>UAS:6XMyc:p53A</i> (C,G) or <i>UAS:6XMyc:p53B</i> (E,I) six hours after a 30 min heat pulse of <i>hsp70:GAL4</i> or no heat shock controls (B, D, F, H). Scale bars are 100 microns. (J) Quantification of the fluorescence intensity of Caspase-3 (C3) staining in the larval wing discs. Error bars represent S.E.M. for n = 4. ** p≤0.01, **** p≤0.0001. (K) Anti-Myc Western blot for Myc:p53 protein from adult wild type (WT) and different <i>UAS:p53</i> P element (P) or PhiC31 (PhiC) transgenic lines six hours after a 30 min heat pulse of <i>hsp70:GAL4</i> (HS), or no heat shock (No HS). Anti-alpha tubulin was used as a loading control.</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167798, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.g002", "stats"=>{"downloads"=>1, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Over_expression_of_the_p53B_isoform_but_not_p53A_induces_apoptosis_in_endocycling_cells_/1167798", "title"=>"Over-expression of the p53B isoform, but not p53A, induces apoptosis in endocycling cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:45:48"}
  • {"files"=>["https://ndownloader.figshare.com/files/1672467"], "description"=>"<p>(A) The mCherry tag increases p53-Ch protein in p53 mutant but not wild type mitotic cycling cells. Western blot with anti-p53 to detect endogenous and mCherry-tagged p53 (p53-Ch) protein in 3<sup>rd</sup> instar B–D extracts. Lane 1: Wild type. Lane 2: Two copies of untagged, wild type p53 BAC transgene in a p53 null mutant background. Lane 3: One copy p53-Ch in a p53 wild type background. Lane 4: One copy p53-Ch in a p53 null background. Lane 5: Two copies p53-Ch in a p53 null background. * indicates a faint non-specific band at ∼72 kDa. ** indicates a degradation product from p53-Ch. Loading control: Anti-alpha Tubulin. (B) RT-qPCR quantification of p53 mRNA expression levels in <i>p53<sup>+</sup></i> or <i>p53-Ch; p53<sup>5A-1-4</sup></i> or <i>p53-Ch; p53<sup>+</sup></i> fly strains. The number of copies for p53 gene is indicated above each genotype. After normalizing to Act5C, the mRNA levels in <i>p53<sup>+</sup></i> were defined as 1. Error bars represent S.E.M from three independent biological replicates. (C) p53-Ch associates with endogenous p53. RFP-nanobody IP from 3<sup>rd</sup> instar B–D extract of the indicated genotypes followed by Western blot with anti-p53. Lane 1,4,7: whole cell extract (WCL), Lane 2,5,8: supernatant (sup) after IP depletion. Lane 3,6,9: IP pellet. * indicates a faint non-specific band at ∼72 kDa. ** indicates a degradation product from p53-Ch. (D) p53 protein level in mitotic cycling B–D cells increases several fold after IR. Western blot with anti-p53 to detect endogenous p53 in 3<sup>rd</sup> instar B–D extracts prepared at different time points after IR. Loading control: Anti-alpha Tubulin. (E) Quantification of p53 protein level change in B–D cells at different time points following IR. After normalizing to loading control alpha-tubulin, p53 protein levels from the No IR control was defined as 1. Error bars represent S.E.M from three independent biological replicates. (F) RT-qPCR quantification of p53 mRNA expression level changes following IR. After normalizing to Act5C, p53 mRNA level from No IR sample was defined as 1. Error bars represent S.E.M from three independent biological replicates.</p>", "links"=>[], "tags"=>["RNA Pol II", "Drosophila polyploid endocycling cells", "p 53A protein stability", "p 53B isoform", "apoptotic response", "cancer polyploid cells", "p 53A isoform", "Drosophila Endocycling Cells Apoptotic cell death", "p 53A protein isoform", "p 53B protein levels", "Drosophila p 53 protein isoforms", "p 53 Target Genes Repress Apoptosis", "dna", "genotoxic stress", "p 53A protein", "p 53 protein", "endocycling cells", "mitotic cycling cells"], "article_id"=>1167858, "categories"=>["Uncategorised"], "users"=>["Bingqing Zhang", "Sonam Mehrotra", "Wei Lun Ng", "Brian R. Calvi"], "doi"=>"https://dx.doi.org/10.1371/journal.pgen.1004581.g006", "stats"=>{"downloads"=>0, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_p53_protein_complex_turnover_in_mitotic_cycling_cells_/1167858", "title"=>"p53 protein complex turnover in mitotic cycling cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-09-11 02:45:48"}

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