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  • JAMA November 3, 2015

    Figure 2: Group A and Group B TP53 Retrogenes in the African Elephant

    A maximum likelihood phylogeny was used to cluster the sequenced TP53 retrogene clones and to confirm the number of unique genes uncovered in the African elephant genome. The phylogeny allows for visualization of TP53 retrogene similarity to one another as well as their relationship to the ancestral TP53 sequence in the elephant and hyrax. The capillary sequenced clones from this study are shown as black circles and published sequences from GenBank are shown as red squares. Gene identifiers and genomic coordinates are given in eTable 2 in the Supplement. Phylogenic analysis reveals at least 18 distinct clusters of processed TP53 copies (shown as colored blocks numbered 1 to 18). These clusters fall into 2 groups, labeled group A and group B. The branch labeled “elephant” is the coding sequence of the ancestral TP53, and “hyrax” represents the coding sequences from the hyrax TP53. The hyrax, on the upper left, is used as the outgroup to show that the hyrax and elephant ancestral TP53 sequences are more similar to each other than to the retrogenes, and also that the retrogenes evolved after the split between hyrax and elephant. The distances between the retrogene sequences display their relationship based on sequence similarity but do not represent precise evolutionary time estimates. These data were generated with DNA from 1 elephant to control for polymorphic bases between individual elephants.
  • JAMA November 3, 2015

    Figure 4: Apoptosis Response Relative to Number of Copies of TP53

    Percentage of apoptosis is shown for peripheral blood lymphocytes treated with 2 Gy of ionizing radiation from 10 individuals with Li-Fraumeni syndrome (with 1 functioning TP53 allele), 10 healthy controls (with 2 TP53 alleles), and 1 African elephant tested in 3 independent experiments (with 40 TP53 alleles). Ionizing radiation–induced apoptosis increased proportionally with additional copies of TP53 and inversely correlated with cancer risk. Experiments performed in quadruplicate for each individual and each colored box represents the mean percentage of cells in late apoptosis as measured by flow cytometry (percentage of annexin V–positive [AV+] and propidium iodide–positive [PI+] treated cells minus AV+PI+ untreated cells). The healthy control lymphocytes underwent more apoptosis than those from LFS patients (P < .001), and elephant lymphocytes underwent more apoptosis than those from healthy controls (P < .001 by 2-sided t test). Horizontal lines indicate the combined mean for all data points in each group with error bars indicating 95% CIs.
  • Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans

    Abstract Full Text
    free access
    JAMA. 2015; 314(17):1850-1860. doi: 10.1001/jama.2015.13134

    This article investigates mechanisms for cancer resistance in elephants and compares cellular response to DNA damage among elephants, healthy human controls, and cancer-prone patients with Li-Fraumeni syndrome.

  • Evolutionary Adaptations to Risk of Cancer: Evidence From Cancer Resistance in Elephants

    Abstract Full Text
    JAMA. 2015; 314(17):1806-1807. doi: 10.1001/jama.2015.13153
  • Identification of a Novel TP53 Cancer Susceptibility Mutation Through Whole-Genome Sequencing of a Patient With Therapy-Related AML

    Abstract Full Text
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    JAMA. 2011; 305(15):1568-1576. doi: 10.1001/jama.2011.473
  • JAMA April 20, 2011

    Figure 4: Transcriptional Activity of Mutant TP53

    A, Human SaOS2 cells were transfected in duplicate with 250-ng wild-type TP53-responsive p50-2Luc promoter-reporter and either 100 ng CMV-Neo (negative control without TP53 expression), wild-type TP53, our patient's TP53, or hot-spot DNA binding mutant p53-R175H. B, Transactivation of the TP53-responsive p50-2Luc promoter was determined 48 hours after transfection. Similar results were obtained with transfection of a greater amount (1 μg) of the TP53 expression constructs (data not shown). C, Expression of well-defined TP53 target genes as determined by RNA expression profiling using Affymetrix Exon 1.0 arrays (Affymetrix, Santa Clara, California). The probe signal values for the t-AML sample and 6 AML samples without TP53 mutations are shown. t-AML indicates therapy-related acute myeloid leukemia.
  • JAMA April 20, 2011

    Figure 1: TP53 Germline Deletion in Patient With t-AML

    A, Changes in sequence read depth indicate a heterozygous and homozygous deletion of TP53 in the skin and bone marrow samples, respectively. B, The deletion (indicated by dotted lines) includes exons 7-9 of TP53 (based on transcript ID ENST00000269305). Genomic coordinates of the deletion boundaries are shown. C, Genomic DNA isolated from the patient's skin or bone marrow or maternal blood was amplified by polymerase chain reaction (PCR) using the 2 primer sets depicted in B. The first primer set (1) produces a 2924–base pair (bp) product from the wild-type but not mutant TP53 allele. The second primer set (2) is predicted to amplify 4169-bp and 1179-bp products from the wild-type and mutant TP53 alleles, respectively. However, because of its smaller size, only the mutant band was consistently seen. Ref indicates DNA ladder reference; t-AML, therapy-related acute myeloid leukemia.
  • JAMA April 20, 2011

    Figure 5: Somatic Single-Nucleotide Variants

    A, The therapy-related acute myeloid leukemia (t-AML) leukemic genome was compared with 2 de novo AML genomes without TP53 mutations (AML2 and AML52). Shown on the x-axis are the various possible nucleotide transitions and transversions; the y-axis represents the percentage of mutations across the genome with that type of mutation. B, Frequency of sequence reads for the mutated allele (compared with total sequence reads) for skin and bone marrow DNA. Dashed lines indicate the expected mutant allele frequency for heterozygous clonal mutations.
  • JAMA January 5, 2011

    Figure 6: MicroRNA/TP53 Pathogenetic Model for Human CLL

    A novel pathogenetic model for chronic lymphocytic leukemia (CLL) showing a pathway of microRNAs and protein coding genes that are involved in the development of CLL. The microRNA 15a (miR-15a)/microRNA 16-1 (miR-16-1) cluster, the microRNA 34b (miR-34b)/microRNA 34c (miR-34c) cluster, and the genes tumor protein p53 (TP53), B-cell CLL/lymphoma 2 (BCL2), myeloid cell leukemia sequence 1 (BCL2-related) (MCL1), and zeta-chain (TCR)–associated protein kinase 70kDa (ZAP70) are the main partners in this model. mRNA indicates messenger RNA.
  • JAMA December 22, 2010

    Figure 5: Effect of Methylation on Transcription of KILLIN and PTEN

    Model depicts where the observed methylation resides with respect to both KILLIN and PTEN and shows the regions where TP53 binds for PTEN and is blocked from binding for KILLIN transcriptional activation. mRNA indicates messenger RNA; UTR, untranslated region; bp, base pair.
  • Reactivating

    Abstract Full Text
    JAMA. 2007; 297(9):941-941. doi: 10.1001/jama.297.9.941-c
  • TP53 Gene and Cancer Resistance in Elephants

    Abstract Full Text
    JAMA. 2016; 315(16):1788-1789. doi: 10.1001/jama.2016.0440
  • TP53 Gene and Cancer Resistance in Elephants

    Abstract Full Text
    JAMA. 2016; 315(16):1789-1790. doi: 10.1001/jama.2016.0446
  • TP53 Gene and Cancer Resistance in Elephants

    Abstract Full Text
    JAMA. 2016; 315(16):1789-1789. doi: 10.1001/jama.2016.0449
  • TP53 Gene and Cancer Resistance in Elephants—Reply

    Abstract Full Text
    JAMA. 2016; 315(16):1790-1791. doi: 10.1001/jama.2016.0457
  • Association of a MicroRNA/TP53 Feedback Circuitry With Pathogenesis and Outcome of B-Cell Chronic Lymphocytic Leukemia

    Abstract Full Text
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    JAMA. 2011; 305(1):59-67. doi: 10.1001/jama.2010.1919
  • JAMA January 5, 2011

    Figure 1: Targeting of TP53 by miR-15a and miR-16 and Effects on TP53 Downstream Effectors in Cell Lines and Primary B-Cell Chronic Lymphocytic Leukemia (B-CLL) Samples

    A, Immunoblots showing the protein expression of tumor protein p53 (TP53), B-cell CLL/lymphoma 2 (BCL2), and vinculin (VCL) in MEG-01 cells transfected with microRNA 15a (miR-15a), microRNA 16 (miR-16), their combination, or their antisense oligonucleotides. Cotransfection of miR-15a and miR-16-1 was performed at the same concentration of oligonucleotides per each; therefore, the total amount of transfected microRNAs was doubled with respect to the other lanes. VCL is the normalization standard used to normalize the amount of proteins loaded to each well. The numbers above the blots indicate the intensity of the band expressed as a ratio “gene product (TP53 or BCL2)/VCL” and normalized to “scrambled.” B, Immunoblots showing the protein expression of TP53, cyclin-dependent kinase inhibitor 1A (p21, Cip 1) (CDKN1A), BCL2 binding component 3 (BBC3), BCL2, zeta-chain (TCR)–associated protein minase 70 kDa (ZAP70), and VCL in primary B-cell CLL cells of 3 patients with CLL with a homozygous 13q deletion. Primary leukemic cells were stably infected with a lentiviral vector expressing miR-15a (LV- miR-15a), a lentiviral vector expressing miR-16-1 (LV- miR-16), or an empty lentiviral vector (LV-Empty). VCL is the normalization standard used to normalize the amount of proteins loaded to each well. The numbers above the blots indicate the intensity of the band expressed as ratio “gene product (TP53, CDKN1A, BBC3, BCL2 or ZAP70)/VCL” and normalized to “LV-Empty.”
  • Spectrum of Mutations in BRCA1 , BRCA2 , CHEK2 , and TP53 in Families at High Risk of Breast Cancer

    Abstract Full Text
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    JAMA. 2006; 295(12):1379-1388. doi: 10.1001/jama.295.12.1379
  • JAMA April 20, 2011

    Figure 2:TP53 Messenger RNA Expression in Patient With t-AML and Controls

    A, TP53 messenger RNA (mRNA) expression profiling used Affymetrix Exon 1.0 arrays (Affymetrix, Santa Clara, California). The probe signal value for each exon is plotted from the patient with therapy-related acute myeloid leukemia (t-AML) along with the signal for 6 AML samples without TP53 mutations. There are 2 probe sets for exon 7. B, Reverse-transcription polymerase chain reaction (RT-PCR) of the patient's bone marrow RNA was performed using primers in exons 6 and 11 of TP53. The wild-type (normal control) and mutant TP53 transcripts produced the predicted bands of 614 base pairs (bp) and 204 bp, respectively. C, Sequencing of the mutant band demonstrated the in-frame splicing of exon 6 to exon 10 (beginning with “ATC”). cDNA indicates complementary DNA.
  • JAMA January 5, 2011

    Figure 2: Targeting of TP53 by miR-15a and miR-16

    A, Luciferase reporter assay (as means [error bars indicate 95% confidence intervals] of experiments conducted in sextuplicate) in cells cotransfected with wild-type tumor protein p53 (TP53) 3′-UTR (TP53 wt) and microRNA 15a (miR-15a) or 16 (miR-16). Luciferase activity normalized to scrambled; RLU indicates relative light units. TP53 del indicates deletion of miR-15a/miR-16 binding site on TP53 3′-UTR; TP53 mut indicates mutation of miR-15a/miR-16 binding site on TP53 3′-UTR. P values calculated for miR-15a and miR-16 vs scrambled; values were statistically significant (P < .05) for TP53 wt comparisons only. B, Expression of miR-15a, miR-16, and TP53 messenger RNA (mRNA) in Tet-Off miR-15a/miR-16-1 –inducible HeLa cells as detected by quantified real-time polymerase chain reaction. Results presented as means (error bars indicate 95% confidence intervals) of experiments performed in triplicate. P values calculated for the cells in the presence of doxycycline (indicates reduced expression of the miR-15a/miR-16-1 cluster) vs the cells in the absence of doxycycline (indicates increased expression of the miR-15a/miR-16-1 cluster); all values were statistically significant (P < .05).