دورية أكاديمية
An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression.
| العنوان: | An African-Specific Variant of TP53 Reveals PADI4 as a Regulator of p53-Mediated Tumor Suppression. |
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| المؤلفون: | Indeglia A; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.; Graduate Group in Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Leung JC; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Miller SA; Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Leu JI; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania., Dougherty JF; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Clarke NL; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Kirven NA; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Shao C; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Ke L; Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Lovell S; Del Shankel Structural Biology Center, The University of Kansas, Lawrence, Kansas., Barnoud T; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Lu DY; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Lin C; Program in Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania., Kannan T; Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania., Battaile KP; NYX, New York Structural Biology Center, Upton, New York., Yang THL; Program in Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania., Batista Oliva I; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Claiborne DT; Program in Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania., Vogel P; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee., Liu L; Del Shankel Structural Biology Center, The University of Kansas, Lawrence, Kansas., Liu Q; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Nefedova Y; Program in Immunology, Microenvironment and Metastasis, The Wistar Institute, Philadelphia, Pennsylvania., Cassel J; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Auslander N; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania., Kossenkov AV; Program in Gene Expression and Regulation, The Wistar Institute, Philadelphia, Pennsylvania., Karanicolas J; Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, Pennsylvania., Murphy ME; Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania. |
| المصدر: | Cancer discovery [Cancer Discov] 2023 Jul 07; Vol. 13 (7), pp. 1696-1719. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research |
| مواضيع طبية MeSH: | Genes, p53* , Neoplasms*/genetics , Tumor Suppressor Protein p53*/metabolism, Animals ; Humans ; Mice ; African People/genetics |
| مستخلص: | TP53 is the most frequently mutated gene in cancer, yet key target genes for p53-mediated tumor suppression remain unidentified. Here, we characterize a rare, African-specific germline variant of TP53 in the DNA-binding domain Tyr107His (Y107H). Nuclear magnetic resonance and crystal structures reveal that Y107H is structurally similar to wild-type p53. Consistent with this, we find that Y107H can suppress tumor colony formation and is impaired for the transactivation of only a small subset of p53 target genes; this includes the epigenetic modifier PADI4, which deiminates arginine to the nonnatural amino acid citrulline. Surprisingly, we show that Y107H mice develop spontaneous cancers and metastases and that Y107H shows impaired tumor suppression in two other models. We show that PADI4 is itself tumor suppressive and that it requires an intact immune system for tumor suppression. We identify a p53-PADI4 gene signature that is predictive of survival and the efficacy of immune-checkpoint inhibitors. Significance: We analyze the African-centric Y107H hypomorphic variant and show that it confers increased cancer risk; we use Y107H in order to identify PADI4 as a key tumor-suppressive p53 target gene that contributes to an immune modulation signature and that is predictive of cancer survival and the success of immunotherapy. See related commentary by Bhatta and Cooks, p. 1518. This article is highlighted in the In This Issue feature, p. 1501. (2023 The Authors; Published by the American Association for Cancer Research.) |
| التعليقات: | Comment in: Cancer Discov. 2023 Jul 7;13(7):1518-1520. (PMID: 37416992) |
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| معلومات مُعتمدة: | R00 CA241367 United States CA NCI NIH HHS; T32 GM008216 United States GM NIGMS NIH HHS; R50 CA211199 United States CA NCI NIH HHS; R01 CA102184 United States CA NCI NIH HHS; T32 CA009171 United States CA NCI NIH HHS; R01 CA238611 United States CA NCI NIH HHS; K99 CA252025 United States CA NCI NIH HHS; S10 OD030394 United States OD NIH HHS; P30 CA006927 United States CA NCI NIH HHS; R00 CA252025 United States CA NCI NIH HHS; T32 CA009035 United States CA NCI NIH HHS; P30 DK050306 United States DK NIDDK NIH HHS; P30 CA010815 United States CA NCI NIH HHS |
| المشرفين على المادة: | EC 3.5.3.15 (PADI4 protein, human) EC 3.5.3.15 (Padi4 protein, mouse) 0 (TP53 protein, human) 0 (Tumor Suppressor Protein p53) |
| تواريخ الأحداث: | Date Created: 20230504 Date Completed: 20230720 Latest Revision: 20240207 |
| رمز التحديث: | 20240207 |
| مُعرف محوري في PubMed: | PMC10326602 |
| DOI: | 10.1158/2159-8290.CD-22-1315 |
| PMID: | 37140445 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2159-8290 |
|---|---|
| DOI: | 10.1158/2159-8290.CD-22-1315 |