Alternative titles; symbols
HGNC Approved Gene Symbol: TP53BP2
Cytogenetic location: 1q41 Genomic coordinates (GRCh38): 1:223,779,893-223,845,947 (from NCBI)
Using a yeast 2-hybrid system, Iwabuchi et al. (1994) identified TP53BP2 as a p53 (TP53; 191170)-binding protein. They showed that TP53BP2 binds to wildtype but not to mutant p53 in vitro.
Using the yeast 2-hybrid system to identify proteins interacting with BCL2 (151430), Naumovski and Cleary (1996) isolated a cDNA encoding a 1,005-amino acid protein that they termed BBP. Sequence analysis determined that BBP is identical to TP53BP2. Binding analysis showed that the ankyrin repeats and SH3 domain of TP53BP2 are required for interaction with both p53 and BCL2 and that TP53BP2 cannot bind to both proteins simultaneously. Northern blot analysis revealed expression of a 4.5-kb transcript in erythroid and lymphoid cell lines. In transfected cells, Western blot analysis demonstrated that TP53BP2 is expressed as proteins of approximately 150 and 140 kD. Immunofluorescence analysis showed a punctate vesicular pattern. Confocal microscopy indicated that BCL2 and TP53BP2 colocalize predominantly in the perinuclear region but that each is expressed in other structures in the cytoplasm. However, Naumovski and Cleary (1996) did not detect TP53BP2 protein in any cell lines. Expression of TP53BP2 does not induce apoptosis but does impede cell cycle progression beyond G2/M, as has been observed with p53.
Samuels-Lev et al. (2001) identified the ASPP1 (606455) and ASPP2 genes. ASPP2 encodes a 1,128-amino acid protein that extends the 1,005-amino acid sequence reported for TP53BP2.
By microarray analysis, Jun et al. (2001) demonstrated expression of the TP53BP2 gene in human donor corneas.
Yang et al. (1997) mapped the TP53BP2 gene to 1q42.1 by fluorescence in situ hybridization.
Stumpf (2024) mapped the TP53BP2 gene to chromosome 1q41 based on an alignment of the TP53BP2 sequence (GenBank BC058918) with the genomic sequence (GRCh38).
By immunoblot analysis, Iwabuchi et al. (1998) showed that expression of TP53BP2 or TP53BP1 (605230) enhances the trans-activation function of p53 and induces the expression of p21 (CDKN1A; 116899). Immunofluorescence microscopy demonstrated that TP53BP2 is present only in the cytoplasm, regardless of p53 expression. Western blot analysis of fractionated cells confirmed that whereas p53 is found in both nuclear and cytosolic fractions, TP53BP2 is found only in the cytosol.
Samuels-Lev et al. (2001) determined that the ASPP proteins interact with p53 (191170) and specifically enhance p53-induced apoptosis but not cell cycle arrest. Inhibition of endogenous ASPP function suppressed the apoptotic function of endogenous p53 in response to apoptotic stimuli. ASPPs enhanced the DNA binding and transactivation function of p53 on the promoters of proapoptotic genes in vivo. Two tumor-derived p53 mutants with reduced apoptotic function were defective in cooperating with ASPP in apoptosis induction. Expression of the ASPPs was frequently downregulated in human breast carcinomas expressing wildtype p53 but not in those expressing mutant p53. Samuels-Lev et al. (2001) concluded that ASPPs regulate the tumor suppression function of p53 in vivo.
By yeast 2-hybrid analysis of HeLa cells, Uhlmann-Schiffler et al. (2009) found that DDX42 (613369) interacted with ASPP2. Deletion analysis showed that a C-terminal domain of DDX42 interacted with both a mid-N-terminal region and the C-terminal ankyrin-SH3 region of ASPP2. DDX42 countered the proapoptotic effect of ASPP2 in several human cell lines, and this inhibition required direct interaction between the 2 proteins, was independent of the presence of p53, and appeared to involve sequestration of ASPP2 by DDX42 from the nucleus to the cytoplasm.
Associations Pending Confirmation
For a discussion of a possible association between variation in the TP53BP2 gene and primary open angle glaucoma, see 602143.0001.
Vives et al. (2006) found that Aspp2-null mice were born at less than the expected mendelian frequency. Aspp3-null pups that survived were runty with a domed head shape, and all Aspp3-null pups died around the time of weaning due to a combination of hydrocephalus and heart abnormalities. Aspp2 +/- mice appeared normal and fertile, but they developed spontaneous tumors. Postnatal lethality in Aspp2-null pups and tumor susceptibility in Aspp2 +/- adults increased on a p53 +/- background, and Aspp2- and p53-null mutations were synthetic lethal, indicating that ASPP2 and p53 are genetically linked and share overlapping functions essential in mouse development.
This variant is classified as a variant of unknown significance because its contribution to primary open angle glaucoma (see 137750) has not been confirmed.
In a 3-generation family in which 8 sibs had primary open angle glaucoma, Micheal et al. (2018) identified heterozygosity for a c.109G-A transition (c.109G-A, NM_001031685) in the TP53BP2 gene, resulting in a val37-to-met (V37M) substitution at a highly conserved residue. The mutation was present in all affected sibs and was not found in an unaffected sib. the variant was present in gnomAD 4.0 in 18 alleles (minor allele frequency, 0.00001), always in heterozygosity (Hamosh, 2024). An R102H substitution in the MAPKAPK2 gene (602006) also segregated fully with disease in the family; haplotype analysis indicated that both variants were in the same linkage interval and in cis configuration. Because MAPKAPK2 has minimal expression in the eye, in contrast to TP53BP2, the authors concluded that TP53BP2 was the strongest candidate for disease association in the family. All 8 affected individuals, 6 sisters and 2 brothers, had bilateral glaucoma, with a mean age at diagnosis of 55 years (range, 49 to 60 years). All had open drainage angles on gonioscopy, with glaucomatous optic neuropathy on funduscopy and reproducible compatible glaucomatous visual field loss, and all showed abnormal results on Heidelberg retinal tomography. The mean of the highest intraocular pressures recorded in their medical records was approximately 24 mmHg. Phenotype data and DNA were not available from their deceased parents, and molecular testing was not reported for a paternal aunt who was designated as living and affected in the published pedigree.
Hamosh, A. Personal Communication. Baltimore, Md. 01/29/2024.
Iwabuchi, K., Bartel, P. L., Li, B., Marraccino, R., Fields, S. Two cellular proteins that bind to wild-type but not mutant p53. Proc. Nat. Acad. Sci. 91: 6098-6102, 1994. [PubMed: 8016121] [Full Text: https://doi.org/10.1073/pnas.91.13.6098]
Iwabuchi, K., Li, B., Massa, H. F., Trask, B. J., Date, T., Fields, S. Stimulation of p53-mediated transcriptional activation by the p53-binding proteins, 53BP1 and 53BP2. J. Biol. Chem. 273: 26061-26068, 1998. [PubMed: 9748285] [Full Text: https://doi.org/10.1074/jbc.273.40.26061]
Jun, A. S., Liu, S. H., Koo, E. H., Do, D. V., Stark, W. J., Gottsch, J. D. Microarray analysis of gene expression in human donor corneas. Arch. Ophthal. 119: 1629-1634, 2001. [PubMed: 11709013] [Full Text: https://doi.org/10.1001/archopht.119.11.1629]
Micheal, S., Saksens, N. T. M., Hogewind, B. F., Khan, M. I., Hoyng, C. B., den Hollander, A. I. Identification of TP53BP2 as a novel candidate gene for primary open angle glaucoma by whole exome sequencing in a large multiplex family. Molec. Neurobiol. 55: 1387-1395, 2018. [PubMed: 28150229] [Full Text: https://doi.org/10.1007/s12035-017-0403-z]
Naumovski, L., Cleary, M. L. The p53-binding protein 53BP2 also interacts with Bc12 and impedes cell cycle progression at G2/M. Molec. Cell Biol. 16: 3884-3892, 1996. [PubMed: 8668206] [Full Text: https://doi.org/10.1128/MCB.16.7.3884]
Samuels-Lev, Y., O'Connor, D. J., Bergamaschi, D., Trigiante, G., Hsieh, J.-K., Zhong, S., Campargue, I., Naumovski, L., Crook, T., Lu, X. ASPP proteins specifically stimulate the apoptotic function of p53. Molec. Cell 8: 781-794, 2001. [PubMed: 11684014] [Full Text: https://doi.org/10.1016/s1097-2765(01)00367-7]
Stumpf, A. M. Personal Communication. Baltimore, Md. 01/29/2024.
Uhlmann-Schiffler, H., Kiermayer, S., Stahl, H. The DEAD box protein Ddx42p modulates the function of ASPP2, a stimulator of apoptosis. Oncogene 28: 2065-2073, 2009. [PubMed: 19377511] [Full Text: https://doi.org/10.1038/onc.2009.75]
Vives, V., Su, J., Zhong, S., Ratnayaka, I., Slee, E., Goldin, R., Lu, X. ASPP2 is a haploinsufficient tumor suppressor that cooperates with p53 to suppress tumor growth. Genes Dev. 20: 1262-1267, 2006. [PubMed: 16702401] [Full Text: https://doi.org/10.1101/gad.374006]
Yang, J.-P., Ono, T., Sonta, S., Kawabe, T., Okamoto, T. Assignment of p53 binding protein (TP53BP2) to human chromosome band 1q42.1 by in situ hybridization. Cytogenet. Cell Genet. 78: 61-62, 1997. [PubMed: 9345910] [Full Text: https://doi.org/10.1159/000134630]