The TP53BP2 gene spans about 66 kb on chromosome 1q42.1 on the minus strand (Yang et al., 1997). There are two transcripts as a result of alternative splicing (Takahashi et al., 2004). The transcript variant 1, which is shorter (4670 bp), does not contain exon 3 and gives rise to a longer form of the protein named TP53BPL (long) or ASPP2. The transcript variant 2, which is longer (4802 bp), contains exon 3 which harbors a stop codon. As a result, the transcription initiates at exon 6 giving rise to a shorter form of the protein named TP53BPS (short) or BBP.

ASPP2 is a serum inducible protein and subject to transcriptional regulation by E2F and its family members (Chen et al., 2005; Fogal et al., 2005).

Not known.

ASPP2 is a pro-apoptotic protein with a predicted size of approximately 135 kDa. It is the founding member of a family of ASPP proteins that all share the common motifs of four Ankyrin-repeats, a Src-homology 3 (SH3) domain, and a Polyproline domain in their C-terminus (Iwabuchi et al., 1994). The N-terminus of ASPP2 is thought to be important for regulating its apoptotic function and contains a putative Ras-association domain as well as a ubiquitin-like fold (Tidow et al., 2007). ASPP2 has been most widely studied for its ability to interact with and stimulate the apoptotic function of the tumor suppressor p53 (and p63/p73) but several studies have also demonstrated p53-independent as well as apoptosis-independent functions for ASPP2 as well (Kampa et al., 2009a).
ASPP2 was originally pulled out of a yeast two-hybrid screen using the p53-binding domain as bait as a partial C-terminal clone named 53BP2 (Iwabuchi et al., 1994). In 1996, Naumovski and Cleary determined that 53BP2 was a partial clone of a longer transcript they named Bcl-2 binding protein (Bbp or Bbp/53BP2) for its ability to bind the anti-apoptotic protein Bcl-2. It was later determined that Bbp is a splice isoform of the full length gene product from this locus, ASPP2 (Samuels-Lev et al., 2001).

Northern blot analysis, using a C-terminal probe, shows elevated levels of ASPP2 mRNA in several human tissues including heart, testis, and peripheral blood leukocytes (Yang et al., 1999). ASPP2 protein levels are controlled by proteasomal degradation (Zhu et al., 2005).

ASPP2 contains a nuclear localization signal within its ankyrin repeat domain (amino acid residues 795-894) that when expressed alone or as a fusion with other proteins localizes in the nucleus of cells (Sachdev et al., 1998; Yang et al., 1999). Despite this signal however, full length ASPP2 is predominantly located in the cytoplasm and often seen near the cell periphery (Naumovski and Cleary, 1996; Iwabuchi et al., 1998; Yang et al., 1999).

Apoptosis. Before ASPP2 was known to be the full length gene product from the TP53BP2 locus, Yang and colleagues showed that overexpression of Bbp/53BP2 in cells induces apoptosis (Yang et al., 1999). In 2000, Lopez et al. demonstrated that Bbp/53BP2 was UV-damage inducible and that loss of this endogenous protein promotes cell survival in response to damage, thus implicating a function in the damage response pathway. In 2001, Samuels-Lev et al. provided evidence that not only does full length ASPP2 promote apoptosis but that it does so, at least in part, through a p53-mediated mechanism that may involve preferential binding of p53 to its apoptotic target genes. ASPP2 has also been shown to modulate the apoptotic activity of the p53 family members, p63/p73 (Bergamaschi et al., 2004), and is known to bind other proteins involved in apoptosis such as Bcl-2 and NF-kappaB (Naumovski and Cleary, 1996; Yang et al., 1999). However, the functional ramifications of these interactions remain unclear. Additionally, there is evidence to indicate ASPP2 as a player in mitochondrial-mediated apoptosis (Kobayashi et al., 2005).
Tumor suppressor. Several clinical studies demonstrate low ASPP2 expression in a variety of human tumors (breast, lung, lymphoma) and this low expression often correlates with poor clinical outcome, suggesting that ASPP2 may function as a tumor suppressor (Mori et al., 2000; Samuels-Lev et al., 2001; Lossos et al., 2002; Cobleigh et al., 2005). In support of this concept, Iwabuchi et al. demonstrated in 1998 that transfection of 53BP2 inhibits Ras/E1A-mediated transformation in rat embryonic fibroblasts. Since then two separate mouse models targeting the ASPP2 locus via homologous recombination have demonstrated that loss of only one copy of ASPP2 increases spontaneous and irradiation-induced tumor formation in vivo (Vives et al., 2006; Kampa et al., 2009b). Taken together these data strongly suggest that ASPP2 is a haplo-insufficient tumor suppressor.
Cell cycle. Bbp, a splice isoform of ASPP2, can induce accumulation of cells in G2/M and thus impede cell cycle progression (Naumovski and Cleary, 1996). Additionally, ASPP2 appears to play a role in the G0/G1 cell cycle checkpoint in response to gamma-irradiation as murine thymocytes that lack one copy of the ASPP2 locus did not arrest at G0/G1 as efficiently as wild type thymocytes (Kampa et al., 2009b).
Cell polarity. ASPP2 is often seen near the cell periphery and has been shown to co-localize with and bind to the tight junction protein PAR-3. Furthermore, loss of ASPP2 expression correlates with a loss of tight junction integrity and an impaired ability to maintain apical domains in polarized cells in culture (Cong et al., 2010). Interestingly these findings hold true in vivo as well. ASPP2 co-localizes with the PAR-3 complex and apical junctions in the brain and is necessary for tight junction integrity. Targeted deletion of ASPP2 in the mouse leads to defects associated with a loss of structural organization in the brain and retina (Sottocornola et al., 2010).
Senescence. Senescence, a type of irreversible cell cycle arrest, is considered an intrinsic protective response against malignant transformation. Wang et al. recently identified ASPP2 as a mediator of Ras-induced senescence by demonstrating that mouse embryonic fibroblasts with a targeted deletion of exon 3 of the ASPP2 gene (TP53BP2) are less prone to senescence in the presence of activated Ras as compared to wild type fibroblasts (as measured by beta-galactosidase staining). Data also suggests that Ras-induced senescence may be mediated by ASPP2 through its ability to inhibit Ras from inducing accumulation of cyclin D1 in the nucleus (Wang et al., 2011).

ASPP2 is a member of the ASPP family of proteins that share a significant amount of homology in their C-terminal domains. ASPP1, ASPP2, and the splice isoform of ASPP2, BBP, share homology in both their N-terminal and C-terminal domains while the family member iASPP only retains C-terminal homology (Samuels-Lev et al., 2001; Bergamaschi et al., 2003).

No mutations at the ASPP2 locus, TP53BP2, have been reported. However, single nucleotide polymorphisms in TP53BP2 have been found associated with gastric cancer susceptibility (Ju et al., 2005) and epigenetic silencing of the promoter by methylation is frequently observed (Sarraf and Stancheva, 2004; Liu et al., 2005; Zhao et al., 2010).