Mapping the P53 Transcriptome Universe Using P53 Natural Polymorphs

Overview

Journal Cell Death Differ

Specialty Cell Biology

Date 2013 Oct 1

PMID 24076587

Citations 36

Authors

B Wang

D Niu

T H Lam

Z Xiao

E C Ren

Affiliations

Soon will be listed here.

Abstract

The tumor suppressor p53 has defined roles in varied cellular processes including apoptosis and DNA repair. While conventional genomic approaches have suggested a large number of p53 targets, there is a need for a systematic approach to validate these putative genes. We developed a method to identify and validate p53's transcriptional behavior by utilizing 16 non-synonymous p53 single-nucleotide polymorphism (SNP) variants. Five SNPs located within the DNA-binding domain of p53 were found to be functionally null, whereas the other 11 SNPs were p53WT-like in behavior. By integrating p53 ChIP-seq analysis with transcriptome data from the p53 SNP variants, 592 genes were identified as novel p53 targets. Many of these genes mapped to previously less well-characterized aspects of p53 function, such as cell signalling, metabolism, central nervous system, and immune system. These data provide pivotal insights into the involvement of p53 in diverse pathways of normal physiological processes and open new avenues for investigation of p53 function.

Citing Articles

The Ashkenazi-Centric G334R Variant of is Severely Impaired for Transactivation but Retains Tumor Suppressor Function in a Mouse Model.

Stieg D, Casey K, Karisetty B, Leu J, Larkin F, Vogel P Mol Cell Biol. 2024; 44(12):607-621.

PMID: 39520074 PMC: 11583612. DOI: 10.1080/10985549.2024.2421885.

TP53 Mutations in AML Patients Are Associated with Dismal Clinical Outcome Irrespective of Frontline Induction Regimen and Allogeneic Hematopoietic Cell Transplantation.

Zhao D, Zarif M, Zhou Q, Capo-Chichi J, Schuh A, Minden M Cancers (Basel). 2023; 15(12).

PMID: 37370821 PMC: 10296444. DOI: 10.3390/cancers15123210.

Successful Retreatment With Venetoclax in a Patient With Chronic Lymphocytic Leukemia.

Jackson R, Smith V, Jayne S, Drewes C, Bens S, Siebert R Hemasphere. 2022; 6(8):e752.

PMID: 35935612 PMC: 9351936. DOI: 10.1097/HS9.0000000000000752.

p53 induces a survival transcriptional response after nucleolar stress.

Liao H, Gaur A, Mauvais C, Denicourt C Mol Biol Cell. 2021; 32(20):ar3.

PMID: 34319761 PMC: 8684752. DOI: 10.1091/mbc.E21-05-0251.

The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes.

Taghadosi M, Adib M, Jamshidi A, Mahmoudi M, Farhadi E Immunol Res. 2021; 69(3):225-238.

PMID: 33983569 DOI: 10.1007/s12026-021-09202-7.

References

Kim C, Delepine M, Boutet E, El Mourabit H, Le Lay S, Meier M . Association of a homozygous nonsense caveolin-1 mutation with Berardinelli-Seip congenital lipodystrophy. J Clin Endocrinol Metab. 2008; 93(4):1129-34. DOI: 10.1210/jc.2007-1328. View

Brady C, Attardi L . p53 at a glance. J Cell Sci. 2010; 123(Pt 15):2527-32. PMC: 2912460. DOI: 10.1242/jcs.064501. View

Kim K, Kang K, Seu Y, Baek S, Kim J . Interferon-gamma induces cellular senescence through p53-dependent DNA damage signaling in human endothelial cells. Mech Ageing Dev. 2008; 130(3):179-88. DOI: 10.1016/j.mad.2008.11.004. View

Langmead B, Trapnell C, Pop M, Salzberg S . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10(3):R25. PMC: 2690996. DOI: 10.1186/gb-2009-10-3-r25. View

Jen K, Cheung V . Identification of novel p53 target genes in ionizing radiation response. Cancer Res. 2005; 65(17):7666-73. DOI: 10.1158/0008-5472.CAN-05-1039. View

Pise-Masison C, Radonovich M, Dohoney K, Morris J, OMahony D, Lee M . Gene expression profiling of ATL patients: compilation of disease-related genes and evidence for TCF4 involvement in BIRC5 gene expression and cell viability. Blood. 2009; 113(17):4016-26. PMC: 2673128. DOI: 10.1182/blood-2008-08-175901. View

Vassilev L, Vu B, Graves B, Carvajal D, Podlaski F, Filipovic Z . In vivo activation of the p53 pathway by small-molecule antagonists of MDM2. Science. 2004; 303(5659):844-8. DOI: 10.1126/science.1092472. View

Morinobu A, Gadina M, Strober W, Visconti R, Fornace A, Montagna C . STAT4 serine phosphorylation is critical for IL-12-induced IFN-gamma production but not for cell proliferation. Proc Natl Acad Sci U S A. 2002; 99(19):12281-6. PMC: 129436. DOI: 10.1073/pnas.182618999. View

Dunn G, Koebel C, Schreiber R . Interferons, immunity and cancer immunoediting. Nat Rev Immunol. 2006; 6(11):836-48. DOI: 10.1038/nri1961. View

10.

Riley T, Sontag E, Chen P, Levine A . Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol. 2008; 9(5):402-12. DOI: 10.1038/nrm2395. View

11.

OFarrell T, Ghosh P, Dobashi N, Sasaki C, Longo D . Comparison of the effect of mutant and wild-type p53 on global gene expression. Cancer Res. 2004; 64(22):8199-207. DOI: 10.1158/0008-5472.CAN-03-3639. View

12.

Vousden K, Prives C . Blinded by the Light: The Growing Complexity of p53. Cell. 2009; 137(3):413-31. DOI: 10.1016/j.cell.2009.04.037. View

13.

Shiels A, Bennett T, Knopf H, Maraini G, Li A, Jiao X . The EPHA2 gene is associated with cataracts linked to chromosome 1p. Mol Vis. 2008; 14:2042-55. PMC: 2582197. View

14.

Lee M, Kuo F, Whitmore G, Sklar J . Importance of replication in microarray gene expression studies: statistical methods and evidence from repetitive cDNA hybridizations. Proc Natl Acad Sci U S A. 2000; 97(18):9834-9. PMC: 27599. DOI: 10.1073/pnas.97.18.9834. View

15.

Miled C, Pontoglio M, Garbay S, Yaniv M, Weitzman J . A genomic map of p53 binding sites identifies novel p53 targets involved in an apoptotic network. Cancer Res. 2005; 65(12):5096-104. DOI: 10.1158/0008-5472.CAN-04-4232. View

16.

Saramaki A, Banwell C, Campbell M, Carlberg C . Regulation of the human p21(waf1/cip1) gene promoter via multiple binding sites for p53 and the vitamin D3 receptor. Nucleic Acids Res. 2006; 34(2):543-54. PMC: 1351372. DOI: 10.1093/nar/gkj460. View

17.

Nikulenkov F, Spinnler C, Li H, Tonelli C, Shi Y, Turunen M . Insights into p53 transcriptional function via genome-wide chromatin occupancy and gene expression analysis. Cell Death Differ. 2012; 19(12):1992-2002. PMC: 3504713. DOI: 10.1038/cdd.2012.89. View

18.

Lefort K, Mandinova A, Ostano P, Kolev V, Calpini V, Kolfschoten I . Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases. Genes Dev. 2007; 21(5):562-77. PMC: 1820898. DOI: 10.1101/gad.1484707. View

19.

Takaoka A, Hayakawa S, Yanai H, Stoiber D, Negishi H, Kikuchi H . Integration of interferon-alpha/beta signalling to p53 responses in tumour suppression and antiviral defence. Nature. 2003; 424(6948):516-23. DOI: 10.1038/nature01850. View

20.

Thierfelder W, Van Deursen J, Yamamoto K, Tripp R, Sarawar S, Carson R . Requirement for Stat4 in interleukin-12-mediated responses of natural killer and T cells. Nature. 1996; 382(6587):171-4. DOI: 10.1038/382171a0. View