TP53BP2

Apoptosis-stimulating of p53 protein 2 (ASPP2) also known as Bcl2-binding protein (Bbp) and tumor suppressor p53-binding protein 2 (p53BP2) is a is_associated_with::protein that in humans is encoded by the TP53BP2 is_associated_with::gene. Multiple transcript variants encoding different isoforms have been found for this gene.

Nomenclature
ASPP2 (amino acid residues 600 –1128) was initially identified as 53BP2 (p53-binding protein 2) in a is_associated_with::yeast two hybrid screen using is_associated_with::p53 as the bait. Another yeast two hybrid screening in which is_associated_with::Bcl-2 was used as the bait gave rise to the discovery of another fragment of ASPP2 (residues 123-1128) and it was called Bbp. The full length ASPP2 (1128 amino acids) was identified later.

Function
ASPP2 plays a central role in regulation of is_associated_with::apoptosis and is_associated_with::cell growth via its interactions. ASPP2 regulates is_associated_with::TP53 by enhancing the is_associated_with::DNA binding and transactivation function of is_associated_with::TP53 on the promoters of proapoptotic is_associated_with::genes in vivo. ASPP2 binds to is_associated_with::wild-type is_associated_with::p53 but fails to bind to is_associated_with::mutant is_associated_with::p53, suggesting that ASPP2 may be involved in the ability of wild-type p53 to suppress transformation. ASPP2 induces apoptosis but no cell cycle arrest.

Structure
ASPP2 contains several structural and functional domains. Its is_associated_with::N-terminus (residues 1–83) has the structure of a β-grasp ubiquitin-like fold. It is followed by a predicted α-helical domain located between aa 123 and 323. and a proline-rich (ASPP2 Pro) domain between aa 674 and 902. The C-terminal part of ASPP2 contains four is_associated_with::ankyrin repeats and an is_associated_with::SH3 domain involved in protein-protein interactions. ASPP2 is found in the perinuclear region of the is_associated_with::cytoplasm.

Family members
The ASPP family includes ASPP1, ASPP2, and iASPP. The name ASPP stands for apoptosis stimulating protein of p53, the name emphasizes the is_associated_with::ankyrin repeats, is_associated_with::SH3 domain, and proline-rich domains that characterize this family. The three family members come from different genes but ASPP1 and ASPP2 share a greater sequence similarity than either does with iASPP as the N terminus of iASPP has no homology with ASPP1 and ASPP2. The sequence similarities among ASPP family members indicates that ASPP1 and ASPP2 probably have similar biological functions that differ from that of iASPP. The family plays a key role in is_associated_with::apoptosis regulation in the is_associated_with::intrinsic and is_associated_with::extrinsic apoptotic pathways. ASPP1 and ASPP2 promote, while iASPP inhibits, is_associated_with::apoptosis.

Binding partners
ASPP2 is the ASPP family member with the most known binding partners. The highly conserved C-terminus was first known to bind to p53 through its is_associated_with::ankyrin repeats and is_associated_with::SH3 domain in 1994 by a is_associated_with::yeast two hybrid system and it was called p53 Binding Protein 2 (53BP2). Other binding partners have been discovered through the years, indicating the importance of the is_associated_with::ankyrin repeats and SH3 domains for is_associated_with::protein-protein interactions. Some of the known binding partners of ASPP2 include is_associated_with::BCL2, p63, is_associated_with::p73, Hepatitis C virus core protein,Amyloid-b-Precursor Protein-Binding Protein 1 (APP-BP1), YES-Associated Protein (YAP), Adenomatosis Polyposis Coli 2 (APC2), RelA/p65,Protein Phosphatase 1 (PP1) and NFκB (p65)

Expression
The expression of ASPP2 is encoded by the gene TP53BP2 and is located in the long arm of is_associated_with::chromosome 1 at q42.1. Northern-blot analyses showed that the ASPP2/53BP2 is_associated_with::mRNA was expressed in many human tissues such as heart, brain, is_associated_with::placenta, lung, liver, is_associated_with::skeletal muscle, kidney, is_associated_with::pancreas, but at varying levels. The highest expression level of ASPP2 was detected in skeletal tissue.

Clinical significance
ASPP2 was first associated with human is_associated_with::cancer when the is_associated_with::crystal structure of is_associated_with::p53 binding domain bound to the is_associated_with::C-terminal is_associated_with::ankyrin repeats and is_associated_with::SH3 domain of ASP2. All the is_associated_with::amino acids of is_associated_with::p53 that are important for binding ASPP2 are mutated in human is_associated_with::cancers. ASPP2 expression levels have been associated with cellular sensitivity to apoptosis. ASPP2 importance in human is_associated_with::malignancies is emphasized by studies that show that is_associated_with::downregulation of ASPP2 is commonly found in is_associated_with::tumors and is_associated_with::carcinoma cells expressing is_associated_with::wild type is_associated_with::p53, and to a lesser extent is_associated_with::mutant is_associated_with::p53. For example, it was found to be is_associated_with::downregulated in both is_associated_with::metastatic and invasive cells as compared to normal breast epithelium. It has been demonstrated the binding of ASPP2 to is_associated_with::bcl-2 and is_associated_with::p53 and to impede is_associated_with::cell cycle progression at G2-M, as well as the fact that binding of ASPP2 to is_associated_with::p53 changes the conformation of is_associated_with::p53 and increases is_associated_with::p53 binding to the promoters of proapoptotic genes such as Bax and PIG-3 but not those of G1-arrest is_associated_with::genes such as p21waf1. Single is_associated_with::nucleotide polymorphisms of ASPP2 have also shown to be associated with predisposition of is_associated_with::gastric cancer development. These could be due to the fact that ASPP2 is also a is_associated_with::tumor suppressor as well as an activator of is_associated_with::p53.

Levels of expression of ASPP2 are important, high levels of expression play an important role in inducing is_associated_with::apoptosis independently of p53, mediated by p63 and p73. The expression is enhanced in response to DNA damage. On the other hand, silencing of ASPP2 expression by methylation was observed in several human carcinoma cells.