Disease relevance of TP53BP2

• We investigated the association of the TP53BP2 locus with gastric cancer susceptibility in a Korean population [1].
• Aberrant overexpression of 53BP2 mRNA in lung cancer cell lines [2].
• Distinct residues of human p53 implicated in binding to DNA, simian virus 40 large T antigen, 53BP1, and 53BP2 [3].
• Apoptosis factor EI24/PIG8 is a novel endoplasmic reticulum-localized Bcl-2-binding protein which is associated with suppression of breast cancer invasiveness [4].
• Expression of a signaling-deficient dominant negative BBP mutant suppressed sensitivity of human Ntera-2 neurons to beta-amyloid peptide mediated toxicity [5].

Psychiatry related information on TP53BP2

• These findings suggest that BBP is a target of neurotoxic beta-amyloid peptide and provide new insight into the molecular pathophysiology of Alzheimer's disease [5].

High impact information on TP53BP2

• The core domain contains the sequence-specific DNA binding activity and the in vitro 53BP2 protein binding activity of p53 [6].
• In the absence of MBD1, H3-K9 methylation is lost at multiple genomic loci and results in activation of p53BP2 gene, normally repressed by MBD1 in HeLa cells [7].
• ASPP1 is a protein homologous to 53BP2, the C-terminal half of ASPP2 [8].
• Nip3 (nineteen kD interacting protein-3) is an E1B 19K and Bcl-2 binding protein of unknown function [9].
• The E1B 19K/Bcl-2-binding protein Nip3 is a dimeric mitochondrial protein that activates apoptosis [9].

Biological context of TP53BP2

• We assayed 9 single nucleotide polymorphisms (SNP) in an 82.5 kb region that included the TP53BP2 locus in 233 male gastric cancer patients and 390 unaffected healthy male controls [1].
• The TP53BP2 gene encodes two splicing variants, 53BP2S and 53BP2L, previously known as apoptosis stimulating protein 2 of p53 (ASPP2) [10].
• We have previously found that the TP53BP2 gene encoding 53BP2 protein is a single copy gene and has been mapped to the long arm of chromosome 1 at q42 [11].
• Assignment of p53 binding protein (TP53BP2) to human chromosome band 1q42.1 by in situ hybridization [12].
• BBP/53BP2 mRNA is abundant in most cell lines examined, but the protein cannot be stably expressed in a variety of cell types by transfection [13].

Anatomical context of TP53BP2

• Furthermore, we demonstrate that 53BP2 is located in the mitochondria and induces apoptosis associated with depression of the mitochondrial trans-membrane potential (DeltaPsim) and activation of caspase-9 [10].
• Likewise, expression of a tetracycline-regulated wild-type p53 cDNA in p53-null fibroblasts caused a reduction in 53BP2 protein levels [14].
• Lower levels of 53BP2 expression sensitized cells to apoptosis induced by DNA damaging chemotherapy agents doxorubicin, ara-C and VP16, but not microtubule active agents paclitaxel and vinblastine [15].
• Apoptosis stimulating protein of p53 (ASPP2) expression differs in diffuse large B-cell and follicular center lymphoma: correlation with clinical outcome [16].
• Nitric oxide suppresses the expression of Bcl-2 binding protein BNIP3 in hepatocytes [17].

Associations of TP53BP2 with chemical compounds

• However, 53BP2 levels were not reduced if the tetracycline-regulated p53 cDNA was expressed after UV damage in these cells [14].
• To address the physiologic significance of 53BP2 induction, we utilized stable cell lines with a ponasterone A-regulated 53BP2 cDNA [14].
• Surprisingly, alanine substitution at the mutational hot spot R175 did not affect DNA binding, transactivation, or T-antigen binding, although it nearly eliminated binding to 53BP1 and 53BP2 [3].
• Estrogen neuroprotection: the involvement of the Bcl-2 binding protein BNIP2 [18].

Physical interactions of TP53BP2

• The core competed with p53 in binding to ASPP2 in vitro [19].

Regulatory relationships of TP53BP2

• ASPP2 can specifically stimulate the apoptotic function of p53 but not cell cycle arrest, but the mechanism of enhancing the activation of pro-apoptotic genes over cell cycle arrest genes remains unknown [20].

Other interactions of TP53BP2

• ASPP1 and ASPP2 are new transcriptional targets of E2F [21].
• However, coexpression of the core with p53 and ASPP2 increased the number of surviving cells [19].
• APCL, a central nervous system-specific homologue of adenomatous polyposis coli tumor suppressor, binds to p53-binding protein 2 and translocates it to the perinucleus [22].
• An in vitro binding assay indicated that the Src-homology-3 domain and the ankyrin-repeat domain of 53BP2 were both required for binding to the COOH-terminus of APCL [22].
• We also show that ASPP2 activates nuclear factor-kappaB (NF-kappaB) transcriptional activity, which seems to be inhibited by the neddylation pathway since the dominant negative NEDD8 activating enzyme causes enhanced NF-kappaB activity [23].

Analytical, diagnostic and therapeutic context of TP53BP2

• Confocal microscopy showed that APCL and 53BP2 proteins were localized together in the perinuclei of normal mammalian cells, but this was not the case in cells that expressed truncated APCL and 53BP2 proteins [22].
• The interaction was confirmed by co-immunoprecipitation of p53BP2 with epitope-tagged PP1 in vitro [24].
• Finally, ASPP1 and ASPP2, molecules involved in mediating the transcription function of p53, were not found to be aberrantly expressed when tested by Northern blot analysis [25].
• Expression of BBP in cell culture induced caspase-dependent vulnerability to beta-amyloid peptide toxicity [5].
• Despite its similarity to 53BP2, RAI did not interact with p53 in a yeast two-hybrid assay [26].

References