» Articles » PMID: 34502215

P53 Activation in Genetic Disorders: Different Routes to the Same Destination

Overview
Journal Int J Mol Sci
Publisher MDPI
Date 2021 Sep 10
PMID 34502215
Citations 8
Authors
Affiliations
Soon will be listed here.
Abstract

The tumor suppressor p53 is critical for preventing neoplastic transformation and tumor progression. Inappropriate activation of p53, however, has been observed in a number of human inherited disorders that most often affect development of the brain, craniofacial region, limb skeleton, and hematopoietic system. Genes related to these developmental disorders are essentially involved in transcriptional regulation/chromatin remodeling, rRNA metabolism, DNA damage-repair pathways, telomere maintenance, and centrosome biogenesis. Perturbation of these activities or cellular processes may result in p53 accumulation in cell cultures, animal models, and perhaps humans as well. Mouse models of several p53 activation-associated disorders essentially recapitulate human traits, and inactivation of p53 in these models can alleviate disorder-related phenotypes. In the present review, we focus on how dysfunction of the aforementioned biological processes causes developmental defects via excessive p53 activation. Notably, several disease-related genes exert a pleiotropic effect on those cellular processes, which may modulate the magnitude of p53 activation and establish or disrupt regulatory loops. Finally, we discuss potential therapeutic strategies for genetic disorders associated with p53 misactivation.

Citing Articles

Functional and Genetic Analyses Unveil the Implication of in Hemifacial Microsomia.

Song W, Xia X, Fan Y, Zhang B, Chen X Int J Mol Sci. 2024; 25(9).

PMID: 38731925 PMC: 11083823. DOI: 10.3390/ijms25094707.


Diphthamide deficiency promotes association of eEF2 with p53 to induce p21 expression and neural crest defects.

Shi Y, Huang D, Song C, Cao R, Wang Z, Wang D Nat Commun. 2024; 15(1):3301.

PMID: 38671004 PMC: 11053169. DOI: 10.1038/s41467-024-47670-1.


DNA damage and repair: underlying mechanisms leading to microcephaly.

Ribeiro J, Altinisik N, Rajan N, Verslegers M, Baatout S, Gopalakrishnan J Front Cell Dev Biol. 2023; 11:1268565.

PMID: 37881689 PMC: 10597653. DOI: 10.3389/fcell.2023.1268565.


The impact of TP53 activation and apoptosis in primary hereditary microcephaly.

Iegiani G, Ferraro A, Pallavicini G, Di Cunto F Front Neurosci. 2023; 17:1220010.

PMID: 37457016 PMC: 10338886. DOI: 10.3389/fnins.2023.1220010.


Identification of 3-Phenylquinoline Derivative PQ1 as an Antagonist of p53 Transcriptional Activity.

Wu X, Wang L, Li Z ACS Omega. 2022; 7(47):43180-43189.

PMID: 36467924 PMC: 9713874. DOI: 10.1021/acsomega.2c05891.


References
1.
Brosh R, Rotter V . When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer. 2009; 9(10):701-13. DOI: 10.1038/nrc2693. View

2.
Liu Y, Deisenroth C, Zhang Y . RP-MDM2-p53 Pathway: Linking Ribosomal Biogenesis and Tumor Surveillance. Trends Cancer. 2017; 2(4):191-204. PMC: 5531060. DOI: 10.1016/j.trecan.2016.03.002. View

3.
Barlow J, Drynan L, Hewett D, Holmes L, Lorenzo-Abalde S, Lane A . A p53-dependent mechanism underlies macrocytic anemia in a mouse model of human 5q- syndrome. Nat Med. 2009; 16(1):59-66. PMC: 2803774. DOI: 10.1038/nm.2063. View

4.
Ceccaldi R, Sarangi P, DAndrea A . The Fanconi anaemia pathway: new players and new functions. Nat Rev Mol Cell Biol. 2016; 17(6):337-49. DOI: 10.1038/nrm.2016.48. View

5.
Turnquist C, Horikawa I, Foran E, Major E, Vojtesek B, Lane D . p53 isoforms regulate astrocyte-mediated neuroprotection and neurodegeneration. Cell Death Differ. 2016; 23(9):1515-28. PMC: 5072428. DOI: 10.1038/cdd.2016.37. View