TP53BP2
Encyclopedia
Apoptosis-stimulating of p53 protein 2 (ASPP2) also known as Bcl2-binding protein (Bbp) and tumor suppressor p53-binding protein 2 (p53BP2) is a protein
that in humans is encoded by the TP53BP2 gene
. Multiple transcript variants encoding different isoforms have been found for this gene.
as the bait. Another yeast two hybrid screening in which 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.
and cell growth
via its interactions. ASPP2 regulates TP53 by enhancing the DNA
binding and transactivation function of TP53 on the promoters of proapoptotic genes
in vivo. ASPP2 binds to wild-type p53
but fails to bind to mutant
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.
s and an SH3 domain
involved in protein-protein interactions. ASPP2 is found in the perinuclear region of the cytoplasm
.
, 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 apoptosis
regulation in the intrinsic and extrinsic apoptotic pathways. ASPP1 and ASPP2 promote, while iASPP inhibits, apoptosis
.
in 1994 by a 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 ankyrin repeats and SH3 domains for protein-protein interactions. Some of the known binding partners of ASPP2 include BCL2, p63
, 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)
, lung, liver, skeletal muscle
, kidney, pancreas
, but at varying levels. The highest expression level of ASPP2 was detected in skeletal tissue.
when the crystal structure
of p53
binding domain bound to the C-terminal ankyrin repeats and SH3 domain
of ASP2. All the amino acids of p53
that are important for binding ASPP2 are mutated in human cancers. ASPP2 expression levels have been associated with cellular sensitivity to apoptosis. ASPP2 importance in human malignancies is emphasized by studies that show that downregulation of ASPP2 is commonly found in tumors and carcinoma
cells expressing wild type
p53
, and to a lesser extent mutant
p53
. For example, it was found to be downregulated in both metastatic and invasive cells as compared to normal breast epithelium. It has been demonstrated the binding of ASPP2 to bcl-2
and p53
and to impede cell cycle progression at G2-M, as well as the fact that binding of ASPP2 to p53
changes the conformation
of p53
and increases p53
binding to the promoters of proapoptotic genes such as Bax
and PIG-3 but not those of G1-arrest genes
such as p21waf1. Single nucleotide
polymorphisms
of ASPP2 have also shown to be associated with predisposition
of gastric cancer development. These could be due to the fact that ASPP2 is also a tumor suppressor as well as an activator
of p53
.
Levels of expression of ASPP2 are important, high levels of expression play an important role in inducing 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.
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
that in humans is encoded by the TP53BP2 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. 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 yeast two hybrid screen using p53P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
as the bait. Another yeast two hybrid screening in which Bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
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 apoptosisApoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
and cell growth
Cell growth
The term cell growth is used in the contexts of cell development and cell division . When used in the context of cell division, it refers to growth of cell populations, where one cell grows and divides to produce two "daughter cells"...
via its interactions. ASPP2 regulates TP53 by enhancing the DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
binding and transactivation function of TP53 on the promoters of proapoptotic genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
in vivo. ASPP2 binds to wild-type p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
but fails to bind to mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, suggesting that ASPP2 may be involved in the ability of wild-type p53 to suppress transformation
Transformation (genetics)
In molecular biology transformation is the genetic alteration of a cell resulting from the direct uptake, incorporation and expression of exogenous genetic material from its surroundings and taken up through the cell membrane. Transformation occurs naturally in some species of bacteria, but it can...
. ASPP2 induces apoptosis but no cell cycle arrest.
Structure
ASPP2 contains several structural and functional domains. Its 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 ankyrin repeatAnkyrin repeat
The ankyrin repeat is a 33-residue motif in proteins consisting of two alpha helices separated by loops, first discovered in signaling proteins in yeast Cdc10 and Drosophila Notch. Ankyrin repeats mediate protein–protein interactions and are among the most common structural motifs in known proteins...
s and an SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
involved in protein-protein interactions. ASPP2 is found in the perinuclear region of the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the 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 ankyrin repeats, SH3 domainSH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
, 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 apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
regulation in the intrinsic and extrinsic apoptotic pathways. ASPP1 and ASPP2 promote, while iASPP inhibits, apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
.
Binding partners
ASPP2 is the ASPP family member with the most known binding partners. The highly conserved C-terminus was fist known to bind to p53 through its ankyrin repeats and SH3 domainSH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
in 1994 by a 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 ankyrin repeats and SH3 domains for protein-protein interactions. Some of the known binding partners of ASPP2 include BCL2, p63
TP73L
Tumor protein p63 also known as transformation-related protein 63 is a protein that in humans is encoded by the TP63 gene.TP63 also known as the p63 gene was discovered 20 years after the discovery of the p53 tumor suppressor gene and along with p73 constitutes the p53 gene family based on their...
, p73
P73
p73 is a protein related to the p53 tumor protein. Because of its structural resemblance to p53, it has also been considered a tumor suppressor. It is involved in cell cycle regulation, and induction of apoptosis. Like p53, p73 is characterized by the presence of different isoforms of the protein...
, 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 chromosome 1 at q42.1. Northern-blot analyses showed that the ASPP2/53BP2 mRNA was expressed in many human tissues such as heart, brain, placentaPlacenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
, lung, liver, skeletal muscle
Skeletal muscle
Skeletal muscle is a form of striated muscle tissue existing under control of the somatic nervous system- i.e. it is voluntarily controlled. It is one of three major muscle types, the others being cardiac and smooth muscle...
, kidney, pancreas
Pancreas
The pancreas is a gland organ in the digestive and endocrine system of vertebrates. It is both an endocrine gland producing several important hormones, including insulin, glucagon, and somatostatin, as well as a digestive organ, secreting pancreatic juice containing digestive enzymes that assist...
, but at varying levels. The highest expression level of ASPP2 was detected in skeletal tissue.
Clinical significance
ASPP2 was first associated with human cancerCancer
Cancer , known medically as a malignant neoplasm, is a large group of different diseases, all involving unregulated cell growth. In cancer, cells divide and grow uncontrollably, forming malignant tumors, and invade nearby parts of the body. The cancer may also spread to more distant parts of the...
when the crystal structure
Crystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...
of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
binding domain bound to the C-terminal ankyrin repeats and SH3 domain
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
of ASP2. All the amino acids of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
that are important for binding ASPP2 are mutated in human cancers. ASPP2 expression levels have been associated with cellular sensitivity to apoptosis. ASPP2 importance in human malignancies is emphasized by studies that show that downregulation of ASPP2 is commonly found in tumors and carcinoma
Carcinoma
Carcinoma is the medical term for the most common type of cancer occurring in humans. Put simply, a carcinoma is a cancer that begins in a tissue that lines the inner or outer surfaces of the body, and that generally arises from cells originating in the endodermal or ectodermal germ layer during...
cells expressing wild type
Wild type
Wild type refers to the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard, "normal" allele at a locus, in contrast to that produced by a non-standard, "mutant" allele...
p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
, and to a lesser extent mutant
Mutant
In biology and especially genetics, a mutant is an individual, organism, or new genetic character, arising or resulting from an instance of mutation, which is a base-pair sequence change within the DNA of a gene or chromosome of an organism resulting in the creation of a new character or trait not...
p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
. For example, it was found to be downregulated in both metastatic and invasive cells as compared to normal breast epithelium. It has been demonstrated the binding of ASPP2 to bcl-2
Bcl-2
Bcl-2 is the founding member of the Bcl-2 family of apoptosis regulator proteins encoded by the BCL2 gene. Bcl-2 derives its name from B-cell lymphoma 2, as it is the second member of a range of proteins initially described in chromosomal translocations involving chromosomes 14 and 18 in...
and p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and to impede cell cycle progression at G2-M, as well as the fact that binding of ASPP2 to p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
changes the conformation
Protein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
and increases p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
binding to the promoters of proapoptotic genes such as Bax
Bcl-2-associated X protein
The Bcl-2–associated X protein, or Bax is a protein of the Bcl-2 gene family. It promotes apoptosis by competing with Bcl-2 proper.The BAX gene was the first identified pro-apoptotic member of the Bcl-2 protein family....
and PIG-3 but not those of G1-arrest genes
Gênes
Gênes is the name of a département of the First French Empire in present Italy, named after the city of Genoa. It was formed in 1805, when Napoleon Bonaparte occupied the Republic of Genoa. Its capital was Genoa, and it was divided in the arrondissements of Genoa, Bobbio, Novi Ligure, Tortona and...
such as p21waf1. Single nucleotide
Nucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
polymorphisms
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
of ASPP2 have also shown to be associated with predisposition
Genetic predisposition
A genetic predisposition is a genetic affectation which influences the phenotype of an individual organism within a species or population but by definition that phenotype can also be modified by the environmental conditions. In the rest of the population, conditions cannot have that effect...
of gastric cancer development. These could be due to the fact that ASPP2 is also a tumor suppressor as well as an activator
Activator (genetics)
An activator is a DNA-binding protein that regulates one or more genes by increasing the rate of transcription. The activator may increase transcription by virtue of a connected domain which assists in the formation of the RNA polymerase holoenzyme, or may operate through a coactivator. A...
of p53
P53
p53 , is a tumor suppressor protein that in humans is encoded by the TP53 gene. p53 is crucial in multicellular organisms, where it regulates the cell cycle and, thus, functions as a tumor suppressor that is involved in preventing cancer...
.
Levels of expression of ASPP2 are important, high levels of expression play an important role in inducing apoptosis
Apoptosis
Apoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
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.