Arnold J. Levine
VerifiedPrinceton University · Molecular Biology
Active 1951–2025
About
Arnold J. Levine is the Harry C. Wiess Professor in the Life Sciences, Emeritus, and a Professor of Molecular Biology, Emeritus, at Princeton University. His research area includes Cell Biology, Development & Cancer. He is associated with the Department of Molecular Biology at Princeton, which features a broad range of research labs and facilities dedicated to molecular biology, biophysics, structural biology, and related fields. His work and contributions are recognized within the department and the broader scientific community, emphasizing his longstanding involvement in advancing understanding in molecular biology and related disciplines.
Research topics
- Biology
- Evolutionary biology
- Genetics
Selected publications
2025-06-03
preprintOpen access<p>Annotated analysis of differential gene expression (DE) from RNA-seq data in NUGC-3 xenografted tumors over 6 days of 100 mg/kg PC14586 administration.</p>
2025-06-03
preprintOpen access<p>Functional characterization of p53-Y220C reactivator compounds and restoration of WT p53 function in cells. <b>A,</b> Structure of p53 reactivators and biochemical properties. The concentration of the test compound required to increase Y220C-DBD binding to the DNA from a consensus p53 response element by 1.5-fold (SC<sub>150</sub>) was measured by the TR-FRET assay; the binding constant (Kd) was determined by surface plasmon resonance (SPR), and the structural stabilization shown by the Tm was determined through a thermal shift assay, as described in Methods. n.d., not determined. <b>B,</b> X-ray crystal structure of the Y220C−PC10709 complex, PDB code <a href="https://www.rcsb.org/structure/9BR3" target="_blank">9BR3</a>. The Y220C protein is shown as a gray cartoon representation with key residues highlighted as stick models. The hydrogen bonds between specific amino acids in the Y220C protein and PC10709 are indicated by dashed red lines. <b>C,</b> Induction of WT p53 antibody reactivity in cells. NUGC-3 cells were treated with PC14586 for 2 hours, followed by IP of p53 with either WT p53 (PAb1620) or mutant p53 (PAb240) cross-reacting antibodies. Changes in WT and mutant cross-reacting p53 levels were detected by Western blotting of the IP samples with the nonspecific 7F5 p53 antibody. <b>D,</b> Fold change in ELISA, normalized to the vehicle control of mutant (PAb240 antibody) and WT (PAb1620 antibody) p53 protein levels in NUGC-3 cells treated for 2 hours with increasing doses of the Y220C reactivator compounds. <b>E,</b> Biotinylated oligonucleotides corresponding to p53 response elements and a negative control (scramble) oligonucleotide were immobilized on an MSD plate and incubated with a cellular lysate from NUGC-3 cells treated with rezatapopt (PC14586; 2 hours). An increase in sequence-specific DNA binding of p53-Y220C was detected with a total p53 antibody. <b>F,</b> A 5-day MTT proliferation assay was performed as described in the Methods section using the four p53 reactivator compounds in NUGC-3 (p53-Y220C), T3M-4 (p53-Y220C), SJSA-1 (p53 WT), and NUGC-3 KO (p53 KO) cells. Proliferation rates and reactivator compound IC<sub>50</sub>s are presented for each cell line. <b>G,</b> The incorporation of EdU and IC<sub>50</sub> was measured following a 24-hour treatment with increasing doses of the reactivator compounds in the indicated cell lines. <b>H,</b> Quantitation of the expression of fluorescently tagged proteins at specific phases of the cell cycle in NUGC-3, T3M-4, and SJSA-1 cells stably expressing the Incucyte Cell Cycle Lentivirus after a 24-hour treatment with 5 µmol/L reactivator compounds and (<b>I</b>) increasing concentrations of rezatapopt (PC14586). <b>J,</b> PC14586 IC<sub>50</sub> values across various cell lines, including those harboring the <i>TP53</i> Y220C mutation or other p53 hotspot mutations, p53 KO cell lines, and p53 WT cell lines, were obtained from a 5-day MTT assay. <b>K,</b> Western blot analysis of p21 and MDM2 protein expression in NUGC-3 and T3M-4 cells following 5-hour PC14586 treatment. Data in D–I were from three experiments, data in J were from two experiments, and graphs were plotted as mean ± SD.</p>
2025-06-03
preprintOpen access<p>p53 pathway profiling analysis in T3M-4 cells treated by PC14586 (5 µM) vs. DMSO control (5 h).</p>
2025-06-03
preprintOpen access<p>p53 pathway profiling analysis in NUGC-3 KO_p53i cells induced with doxycycline (50 ng/ml) vs. PBS control (12.5 h).</p>
Genomic landscape of virus-associated cancers
Nature Communications · 2025-07-01 · 1 citations
articleOpen accessIt has been estimated that 15%-20% of human cancers are attributable to infections, mostly by carcinogenic viruses. The incidence varies worldwide, with a majority affecting developing countries. Here, we conduct a comparative analysis of virus-positive and virus-negative tumors in nine cancers linked to five viruses. We observe a higher frequency of virus-positive tumors in males, with notable geographic differences in incidence. Our genomic analysis of 1971 tumors reveals a lower somatic burden, distinct mutation signatures, and driver gene mutations in virus-positive tumors. Compared to virus-negative cases, virus-positive cases have fewer mutations of TP53, CDKN2A, and deletions of 9p21.3/CDKN2A-CDKN1A while exhibiting more mutations in RNA helicases DDX3X and EIF4A1. Furthermore, an analysis of clinical trials of PD-(L)1 inhibitors suggests an association of virus-positivity with higher treatment response rate, particularly evident in gastric cancer and head and neck squamous cell carcinoma. Both cancer types also show evidence of increased CD8 + T cell infiltration and T cell receptor clonal selection in virus-positive tumors. These results illustrate the epidemiological, genetic, and therapeutic trends across virus-associated malignancies.
2025-06-03
preprintOpen access<p>p53 pathway profiling analysis in NUGC-3 cells treated by PC14586 (5 µM) vs. DMSO control (5 h).</p>
2025-06-03
preprintOpen access<p>The restoration of the p53 signaling pathway in vivo was assessed via p53 pathway profiling analysis in NUGC-3 xenografted tumors after 6 days of 100-mg/kg PC14586 administration.</p>
2025-06-03
preprintOpen access<p>GSEA analysis using MSigDB Hallmark gene sets collection (H) for all detected genes demonstrated the regulation of genes for immune and inflammatory response in vivo in NUGC-3 xenograft tumors following 8 h of treatment with 100 mg/kg PC14586.</p>
2025-06-03
preprintOpen access<p>p53 pathway profiling analysis in NUGC-3 KO cells treated by PC14586 (5 µM) vs. DMSO control (5 h).</p>
2025-06-03
preprintOpen access<p>PC14586 restored multiple facets of dynamic WT p53 transcriptional responses <i>in vivo</i>. <b>A,</b> Time-dependent effects of PC14586 on gene expression of key p53 targets, <i>CDKN1A</i>, <i>MDM2</i>, and <i>BIRC5</i>, with repeat daily administration across 6 days in the NUGC-3 xenograft model. <i>n</i> = 4/group. Error bars show the SEM. The red symbols show plasma concentrations (µmol/L) and are designated on the right <i>y</i>-axis. <b>B,</b> Assessment of a panel of 84 p53 pathway genes measured by qRT-PCR. A representative number of upregulated and downregulated p53 target genes are shown across 6 days of 100 mg/kg PC14586 administration, with the mean value of log<sub>2</sub> (fold change) at each time point shown on the heatmap. See Supplementary File S12 for details. RNA samples extracted from tumor samples, as in <b>A</b>, were profiled by the Qiagen RT<sup>2</sup> p53 pathway qRT-PCR panel as described in the Methods section. Symbols represent the mean log<sub>2</sub> (fold change) for each. <b>C,</b> Volcano plots from RNA-seq analysis of expressed genes from NUGC-3 xenograft tumors following PC14586 (100 mg/kg) and vehicle treatment as indicated. Graphs were plotted as in <a href="#fig2" target="_blank">Fig. 2C</a>, except that the p53-targeted lncRNA (upregulated) gene set was overlaid on top of the others. See Supplementary Fig. S5B for the corresponding scatter plots. In <b>B</b> and <b>C,</b> vehicle (consolidated), <i>n</i> = 12 and PC14586, <i>n</i> = 4 for each group, as in <a href="#fig3" target="_blank">Figs. 3C</a> and <a href="#fig3" target="_blank">D</a> and <a href="#fig4" target="_blank">4A</a>. <b>D,</b> Top enriched gene sets from GSEA of the Molecular Signatures Database C2 collection curated gene sets supplemented with Fischer p53-targeted lncRNA (86 genes; C2+) in the indicated RNA-seq data [rezatapopt (PC14586) for once daily (QD) ×6 at 24 hours] from DEGs. See Supplementary File S14 for details. Gene sets with a normalized enrichment score (NES) and an FDR <i>q</i> value (<i>q</i>) < 0.001 are highlighted in green, 0.001 to 0.05 are highlighted in orange, and 0.05 to 0.06 are highlighted in gray. Graphs were plotted as in <a href="#fig2" target="_blank">Fig. 2D</a>. <b>E,</b> Updated schematic representation of p53 in regulating the cell cycle via retinoblastoma-E2F and DREAM complexes. Updated from <a href="#fig2" target="_blank">Fig. 2F</a>, the lncRNA component was added to complement p21 in regulating the cell cycle. PINCR, p53-induced noncoding RNA.</p>
Recent grants
Roles and Regulation of wild-type and mutant forms of p53
NIH · $3.8M · 2000–2023
NIH · $11.9M · 2012
NIH · $1.0M · 1989
NIH · $1.1M · 1994
Roles and Regulation of wild-type and mutant forms of p53
NIH · $3.5M · 2000–2017
Frequent coauthors
- 170 shared
Alexei Vázquez
- 165 shared
Wenwei Hu
The First People's Hospital of Changzhou
- 152 shared
Gareth L. Bond
- 115 shared
Zhaohui Feng
Rutgers Cancer Institute of New Jersey
- 109 shared
Elisabeth E. Bond
- 101 shared
Gyan Bhanot
Rutgers, The State University of New Jersey
- 92 shared
Lukasz F. Grochola
Kantonsspital Winterthur
- 84 shared
Helge Täubert
Universitätsklinikum Erlangen
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