Disease relevance of Trp53

• Mice inheriting two copies of this mutation (Trp53(515C/515C)) escape the early onset of thymic lymphomas that characterize Trp53-null mice [1].
• Different Trp53 shRNAs produced distinct phenotypes in vivo, ranging from benign lymphoid hyperplasias to highly disseminated lymphomas that paralleled Trp53-/- lymphomagenesis in the E(mu)-Myc mouse [2].
• In contrast, here we present data that mice mutant for Trp53 and Nf1 on a 129S4/SvJae background are highly resistant to developing astrocytoma [3].
• The tumor spectrum in Fancd2(-/-)/Trp53(+/-) mice included sarcomas expected in Trp53 heterozygotes, as well as mammary and lung adenocarcinomas that occur rarely in Trp53 heterozygotes [4].
• Concomitant Trp53+/- mutation cooperated with Mist1(KrasG12D/+) to accelerate lethality and was associated with advanced histopathologic findings, including parenchymal liver metastasis [5].

Psychiatry related information on Trp53

• It is known that upon p53 induction, multiple downstream factors contribute to the decision making between growth arrest and apoptosis [6].
• Genetic interaction between expanded murine Hdh alleles and p53 reveal deleterious effects of p53 on Huntington's disease pathogenesis [7].
• We found that water deprivation leads to simultaneous activation of synthesis of VP and p53 and Bcl-2 apoptotic proteins in the mouse brain [8].
• Here we report that these double mutant mice develop T-cell lymphoma at a significantly reduced latency period compared to single p53 null mice that are already cancer prone [9].
• Intracellular Abeta42 activates p53 promoter: a pathway to neurodegeneration in Alzheimer's disease [10].

High impact information on Trp53

• Furthermore, we show that PRAK activates p53 by direct phosphorylation [11].
• Therefore, NEDD4-1 is a potential proto-oncogene that negatively regulates PTEN via ubiquitination, a paradigm analogous to that of Mdm2 and p53 [12].
• Yet Kras-transformed mouse colonocytes lacking p53 formed indolent, poorly vascularized tumors, whereas additional transduction with a Myc-encoding retrovirus promoted vigorous vascularization and growth [13].
• Using the well-characterized Emu-myc lymphoma model, we show that p53 is spontaneously activated when restored in established Emu-myc lymphomas in vivo, triggering rapid apoptosis and conferring a significant increase in survival [14].
• The cell death was preceded by aberrant accumulation of cell cycle regulators and increased genomic instability and could be partially rescued by removal of the tumor suppressor protein p53 [15].

Chemical compound and disease context of Trp53

• Benzene-induced sarcomas, p-cresidine-induced bladder carcinomas and phenolphthalein-induced thymic lymphomas were allelotyped at the Trp53 locus and chromosome 11 simple sequence length polymorphic (SSLP) loci [16].
• We found that DBA/2xC57BL/6 F2 hybrid mice with the DBA/2 genotype at the Trp53 locus were relatively resistant to tetrachlorodibenzo-p-dioxin toxicity, and this resistance was additive with resistance associated with the Ahr locus [17].
• Cytogenetic findings, Trp53 mutations, and hormone responsiveness in a medroxyprogesterone acetate induced murine breast cancer model [18].
• The genetic modifier Mom1 and the pharmacological agents piroxicam and difluoromethylornithine each reduced intestinal adenoma multiplicity in the absence of p53 function [19].
• Distinct Effects of Annexin A7 and p53 on Arachidonate Lipoxygenation in Prostate Cancer Cells Involve 5-Lipoxygenase Transcription [20].

Biological context of Trp53

• Chromosome stability, in the absence of apoptosis, is critical for suppression of tumorigenesis in Trp53 mutant mice [1].
• Deletion of the Trp53 tumor suppressor gene greatly accelerates Myc-induced lymphomagenesis, resulting in highly disseminated disease [2].
• To define this role in vivo, we generated a Trp53 knock-in construct encoding a protein carrying mutations of two residues that are crucial for transactivation (L25Q,W26S) [21].
• Our interest in the Gas-3 gene was prompted by our previously reported localization of the gene on the mouse chromosome 11.44 +/- 1.9 cM proximal to the Trp53 locus and by the finding, by others, that it codes for a myelin protein and that a point mutation in its fourth putative transmembrane region is associated with the trembler mutation [22].
• Loss of heterozygosity occurs via mitotic recombination in Trp53+/- mice and associates with mammary tumor susceptibility of the BALB/c strain [23].

Anatomical context of Trp53

• Mutational inactivation of Trp53 partially rescues the demethylated fibroblasts for up to five population doublings in culture [24].
• Unexpectedly, elimination of one Trp53 allele completely rescues this embryonic lethality and restores normal mammary gland development [25].
• To determine whether RNAi suppression of Trp53 could produce a similar phenotype, we introduced several Trp53 short hairpin RNAs (shRNAs) into hematopoietic stem cells derived from E(mu)-Myc transgenic mice, and monitored tumor onset and overall pathology in lethally irradiated recipients [2].
• Crossing of Snm1 mutant mice with a Trp53 null mutant resulted in an increase in mortality and a restriction of the tumor type to lymphomas, particularly those of the thymus [26].
• In multiple cell types, including mammary epithelial cells, abrogation of p53 (encoded by Trp53) function is associated with increased tumorigenesis [27].

Associations of Trp53 with chemical compounds

• Double-mutant mice, which have greatly reduced Kit receptor tyrosine kinase activity and also lack Trp53, were generated and the affected cell lineages examined [28].
• Treatment of 2-3-month-old Trp53(-/-), lacZ hybrid mice with the powerful mutagen ethyl nitrosourea (ENU) resulted in a higher number of mutations induced in the liver but not in the spleen, as compared to the Trp53(+/+), lacZ mice [29].
• Although ectopic expression of wild-type p53 blocked cells in the G1 phase of the cell cycle, G1 arrest by isoleucine starvation, in a manner independent of p53, did not confer susceptibility to apoptosis [30].
• MEFs lacking p53 or gadd45 genes exhibited decreased colony-forming ability after UV radiation and cisplatin compared to wild-type MEFs, indicating their sensitivity to DNA damage [31].
• P53 was transiently phosphorylated at serine 23 during liver regeneration in an Atm-dependent manner [32].

Physical interactions of Trp53

• Rather, c-Jun regulates transcription of p53 negatively by direct binding to a variant AP-1 site in the p53 promoter [33].
• We conclude that inactivation of ARF acts more broadly than that of p53 in connecting abrogation of the Rb pathway to tumorigenesis [34].
• The Mdm2 oncoprotein forms a complex with the p53 tumor suppressor protein and inhibits p53-mediated regulation of heterologous gene expression [35].
• BALB/c alleles for Prkdc and Cdkn2a interact to modify tumor susceptibility in Trp53+/- mice [36].
• The promoter assays further confirmed the independency of p53-binding sites in the activation and linked UV-responsive transcriptional regulation of p21 to two Sp1 consensus binding sites within -61 bp of the transcription initiation site [37].

Enzymatic interactions of Trp53

• Polyomavirus large T antigen coprecipitates with p53 phosphorylated on serine 18 and also with p21Cip1/WAF1 [38].
• DNAPK is normally activated by DNA dsbs and phosphorylates the p53 protein [39].
• The co-precipitated complex by the anti-phospho-JNK antibody was capable of phosphorylating intrinsic or extrinsic p53 on Ser-15 [40].
• We found that centrosomal p53 is poly(ADP-ribosyl)ated in vivo and centrosomal PARP-1 directly catalyzes poly(ADP-ribosyl)ation of p53 in vitro [41].
• Recombinant wild-type mouse p53 was phosphorylated in vitro by activated recombinant p42-MAP kinase but not by inactive MAP kinase or by the activating protein, MAP kinase kinase [42].

Regulatory relationships of Trp53

• The protracted latent period before the onset of frank disease likely reflects the ability of c-Myc to induce a p53-dependent apoptotic program that initially protects animals against tumor formation but is disabled when overtly malignant cells emerge [43].
• The p19(ARF) tumor suppressor antagonizes Mdm2 to induce p53-dependent cell cycle arrest [44].
• p53 is required for both radiation-induced differentiation and rescue of V(D)J rearrangement in scid mouse thymocytes [45].
• This indicated that c-Jun controls hepatocyte proliferation by a p53/p21-dependent mechanism [46].
• Here we show that the E2f3 mutation completely suppresses both the inappropriate proliferation and the p53-dependent apoptosis arising in the Rb mutant embryos [47].

Other interactions of Trp53

• Partial rescue of the prophase I defects of Atm-deficient mice by p53 and p21 null alleles [48].
• Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction [49].
• Thus, we have proposed that the reduction in mdm2 expression in Brca1 (5-6) mutants might lead to increased p53 activity [50].
• Whereas induction of p53 involves events in the cell nucleus, the activation of transcription factors AP-1 and NF-kappaB by ultraviolet radiation is mediated through membrane-associated signalling proteins, ruling out a nuclear signal [51].
• Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum [52].

Analytical, diagnostic and therapeutic context of Trp53

• By Southern blotting, 96% (24 of 25) of BALB/c-Trp53(+/-) mammary tumors displayed LOH for Trp53 [23].
• METHODS: Frequencies of murine bone marrow cells (BMCs) with the Lin(-)Sca-1(+)c-kit(+)CD34- phenotype were analyzed by flow cytometry, and were increased in mice with germ-line deletion of the Trp53 (Trp53(-/-)) gene but not in 25 other deletions of genes involved in cell cycling, development, cancer, or hematopoiesis [53].
• Recipients of Trp53(-/-) donors had two to three times more Lin(-)Sca-1(+)c-kit(+)CD34(-) BMCs than recipients of Trp53(+/+) donors at five months after transplantation [53].
• However, the mRNA expression of Trp53 and Cdkn1a (p21) after irradiation was not different among the organ types, and immunohistochemistry revealed that all the organs expressed these two proteins after irradiation [54].
• C57BL/6 Trp53 heterozygous (N5) mice (p53+/- mice) show an increased sensitivity to tumorigenesis following exposure to genotoxic compounds and are being used as an alternate animal model for carcinogenicity testing [55].

References