Protein BTG2 also known as BTG family member 2 or NGF-inducible anti-proliferative protein PC3 or NGF-inducible protein TIS21, is a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...
that in humans is encoded by the ''BTG2''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
(
B-cell
translocation
gene
2)
and in other mammals by the homologous ''Btg2'' gene.
This protein controls
cell cycle
The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
progression and proneural genes expression by acting as a
transcription coregulator
In molecular biology and genetics, transcription coregulators are proteins that interact with transcription factors to either activate or repress the transcription of specific genes. Transcription coregulators that activate gene transcription ar ...
that enhances or inhibits the activity of
transcription factor
In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s.
The protein BTG2 is the human homolog of the PC3 (
pheochromocytoma
cell
3) protein in rat and of the Tis21 (
tetradecanoyl phorbol acetate-
inducible
sequence
21) protein in mouse.
''Tis21'' had been originally isolated as a sequence induced by
TPA in mouse fibroblasts,
whereas ''PC3'' was originally isolated as sequence induced at the beginning of neuron differentiation;
''BTG2'' was then isolated in human cells as sequence induced by
p53
p53, also known as tumor protein p53, cellular tumor antigen p53 (UniProt name), or transformation-related protein 53 (TRP53) is a regulatory transcription factor protein that is often mutated in human cancers. The p53 proteins (originally thou ...
and DNA damage.
The protein encoded by the gene BTG2 (which is the official name assigned to the gene PC3/Tis21/BTG2) is a member of the BTG/Tob family (that comprises six proteins
BTG1
Protein BTG1 is a protein that in humans is encoded by the ''BTG1'' gene.
Function
The BTG1 gene locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. It is a memb ...
, BTG2/PC3/Tis21,
BTG3
Protein BTG3 is a protein that in humans is encoded by the ''BTG3'' gene.
The protein encoded by this gene is a member of the BTG/Tob family. This family has structurally related proteins that appear to have antiproliferative properties. This e ...
/ANA,
BTG4
Protein BTG4 also known as BTG family member 4 is a protein that in humans is encoded by the ''BTG4'' gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucle ...
/PC3B,
Tob1
Protein Tob1 is a protein that in humans is encoded by the ''TOB1'' gene.
Function
This gene encodes a member of the tob/btg1 family of anti-proliferative proteins that have the potential to regulate cell growth. When exogenously expressed, t ...
/Tob and
Tob2
Protein Tob2 (transducer of ERBB2, 2) is a protein that in humans is encoded by the ''TOB2'' gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in ...
).
This family has structurally related proteins that appear to have antiproliferative properties. In particular, the BTG2 protein has been shown to negatively control a cell cycle checkpoint at the
G1 to
S phase
S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S ...
transition in fibroblasts and neuronal cells by direct inhibition of the activity of
cyclin D1
Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene.
Gene expression
The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lo ...
promoter.
Regulator of neuron differentiation
A number of studies in vivo have shown that ''BTG2'' expression is associated with the neurogenic
asymmetric division in
neural progenitor cells.
Tis21-GFP has been used as a neurogenic marker because it is not expressed until neurogenesis begins, is present in almost all early-born neurons, and interacts with neuron producing
intermediate progenitor cell Intermediate progenitor cells (IPCs) are a type of progenitor cell in the developing cerebral cortex. They are multipolar cells produced by radial glial cells who have undergone asymmetric division. IPCs can produce neuron cells via neurogenesis ...
s.
Moreover, when directly overexpressed in vivo in neural progenitor cells, BTG2 induces their differentiation.
In fact, in the neuronal PC12 cell line BTG2 is not able to trigger differentiation by itself, but only to synergize with NGF,
while in vivo BTG2 is fully able to induce differentiation of progenitor cells, i.e., during embryonic development in the
neuroblast
In vertebrates, a neuroblast or primitive nerve cell is a postmitotic cell that does not divide further, and which will develop into a neuron after a migration phase. In invertebrates such as ''Drosophila,'' neuroblasts are neural progenitor cells ...
of the neural tube and in
granule precursors of cerebellum, as well in adult progenitor cells of the
dentate gyrus
The dentate gyrus (DG) is one of the subfields of the hippocampus, in the hippocampal formation. The hippocampal formation is located in the temporal lobe of the brain, and includes the hippocampus (including CA1 to CA4) subfields, and other su ...
and of the
subventricular zone
The subventricular zone (SVZ) is a region situated on the outside wall of each lateral ventricle of the vertebrate brain. It is present in both the embryonic and adult brain. In embryonic life, the SVZ refers to a secondary proliferative zon ...
.
Notably, it has recently been shown that BTG2 is essential for the differentiation of new neurons, using a BTG2
knock out
A knockout (abbreviated to KO or K.O.) is a fight-ending, winning criterion in several Contact sports, full-contact combat sports, such as boxing, kickboxing, Muay Thai, mixed martial arts, karate, some forms of World Taekwondo Federation#Sparri ...
mouse.
BTG2 is thus a pan-neural gene required for the development of the new
neuron
A neuron (American English), neurone (British English), or nerve cell, is an membrane potential#Cell excitability, excitable cell (biology), cell that fires electric signals called action potentials across a neural network (biology), neural net ...
s generated during adulthood, in the two neurogenic regions of adult brain, i.e., the
hippocampus
The hippocampus (: hippocampi; via Latin from Ancient Greek, Greek , 'seahorse'), also hippocampus proper, is a major component of the brain of humans and many other vertebrates. In the human brain the hippocampus, the dentate gyrus, and the ...
and the subventricular zone.
Such requirement of BTG2 in neuron maturation is consistent with the fact that during brain development BTG2 is expressed in the proliferating neuroblasts of the ventricular zone of the neural tube, and to a lower extent in the differentiating neuroblasts of the mantle zone; postnatally it is expressed in cerebellar precursors mainly in the proliferating regions of the neuropithelium (i.e., in the external granular layer), and in the hippocampus in proliferating and differentiating progenitor cells.
The pro-differentiative action of BTG2 appears to be consequent not only to inhibition of cell cycle progression but also to a BTG2-dependent activation of proneural genes in neural progenitor cells.
In fact, BTG2 activates proneural genes by associating with the promoter of
Id3
ID3 is a metadata container most often used in conjunction with the MP3 audio file format. It allows information such as the title, artist, album, track number, and other information about the file to be stored in the file itself.
ID3 is a '' ...
, a key inhibitor of proneural gene activity, and by negatively regulating its activity.
BTG2 is a transcriptional cofactor, given that it has been shown to associate with, and regulate the promoters not only of Id3 but also of
cyclin D1
Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene.
Gene expression
The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lo ...
and
RAR-β
Retinoic acid receptor beta (RAR-beta), also known as NR1B2 (nuclear receptor subfamily 1, group B, member 2) is a nuclear receptor that in humans is encoded by the ''RARB'' gene.
Function
This gene encodes retinoic acid receptor beta, a memb ...
, being part of transcriptional complexes.
It has been shown that when the differentiation of new neurons of the hippocampus - a brain region important for learning and memory - is either accelerated or delayed by means of overexpression or deletion of BTG2, respectively, spatial and contextual memory is heavily altered.
This suggests that the time the young neurons spend in different states of neuronal differentiation is critical for their ultimate function in learning and memory, and that BTG2 may play a role in the timing of recruitment of the new neuron into memory circuits.
In conclusion, the main action of Btg2 on neural progenitor cells of the dentate gyrus and subventricular zone during adult neurogenesis is the positive control of their terminal differentiation (see for review:). During the early postnatal development of the cerebellum, Btg2 is mainly required to control the migration and differentiation of the precursor cells of cerebellar granule neurons. In contrast,
BTG1
Protein BTG1 is a protein that in humans is encoded by the ''BTG1'' gene.
Function
The BTG1 gene locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. It is a memb ...
, the closest homolog to Btg2, appears to negatively regulate the proliferation of adult stem cells in the dentate gyrus and subventricular zone, maintaining in quiescence the stem cells pool and preserving it from depletion.
BTG1
Protein BTG1 is a protein that in humans is encoded by the ''BTG1'' gene.
Function
The BTG1 gene locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. It is a memb ...
is also necessary to limit the proliferative expansion of cerebellar precursor cells, as without
BTG1
Protein BTG1 is a protein that in humans is encoded by the ''BTG1'' gene.
Function
The BTG1 gene locus has been shown to be involved in a t(8;12)(q24;q22) chromosomal translocation in a case of B-cell chronic lymphocytic leukemia. It is a memb ...
the adult cerebellum is larger and unable to coordinate motor activity.
Medulloblastoma suppressor
BTG2 has been shown to inhibit medulloblastoma, the very aggressive tumor of cerebellum, by inhibiting the proliferation and triggering the differentiation of the precursors of cerebellar granule neurons. This demonstration was obtained by overexpressing BTG2 in a mouse model of medulloblastoma, presenting activation of the
sonic hedgehog
Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene.
This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...
pathway (heterozygous for the gene
Patched1).
More recently, it has been shown that the ablation of BTG2 greatly enhances the medulloblastoma frequency by inhibiting the migration of cerebellar granule neuron precursors. This impairment of migration of the precursors of cerebellar granule neurons forces them to remain at the surface of the cerebellum, where they continue to proliferate, becoming target of transforming insults.
The impairment of migration of the precursors of cerebellar granule neurons (GCPs) depends on the inhibition of expression of the chemokine
CXCL3
Chemokine (C-X-C motif) ligand 3 (CXCL3) is a small cytokine belonging to the CXC chemokine family that is also known as ''GRO3 oncogene'' (GRO3), ''GRO protein gamma'' (GROg) and ''macrophage inflammatory protein-2-beta'' (MIP2b). CXCL3 controls ...
consequent to ablation of BTG2. In fact, the transcription of CXCL3 is directly regulated by BTG2, and CXCL3 is able to induce cell-autonomously the migration of cerebellar granule precursors. Treatment with CXCL3 prevents the growth of medulloblastoma lesions in a Shh-type mouse model of medulloblastoma.
Thus, CXCL3 is a target for medulloblastoma therapy.
Interactions
BTG2 has been shown to
interact
Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...
with
PRMT1
Protein arginine N-methyltransferase 1 is an enzyme that in humans is encoded by the ''PRMT1'' gene. The HRMT1L2 gene encodes a protein arginine methyltransferase that functions as a histone methyltransferase specific for histone H4.
Function ...
,
HOXB9
Homeobox protein Hox-B9 is a protein that in humans is encoded by the ''HOXB9'' gene.
Function
This gene is a member of the Abd-B homeobox family and encodes a protein with a homeobox DNA-binding domain. It is included in a cluster of homeobox ...
,
CNOT8
CCR4-NOT transcription complex subunit 8 is a protein that in humans is encoded by the ''CNOT8'' gene. It is a subunit of the CCR4-Not deadenylase complex.
Interactions
CNOT8 has been shown to interact with BTG2, BTG1
Protein BTG1 is a pro ...
and
HDAC1
Histone deacetylase 1 (HDAC1) is an enzyme that in humans is encoded by the ''HDAC1'' gene.
Function
Histone acetylation and deacetylation, catalyzed by multisubunit complexes, play a key role in the regulation of eukaryotic gene expression. ...
HDAC4
Histone deacetylase 4, also known as HDAC4, is a protein that in humans is encoded by the ''HDAC4'' gene.
Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation ...
and
HDAC9
Histone deacetylase 9 is an enzyme that in humans is encoded by the ''HDAC9'' gene.
Function
Histones play a critical role in transcriptional regulation, cell cycle progression, and developmental events. Histone acetylation/deacetylation alter ...
.
It has also been studied with
Pax6 and
Tbr2 when observing the role of Tis21 in neurogenic divisions.
References
Further reading
*
*
*
*
*
*
*
External links
*
*
* {{PDBe-KB2, Q04211, Mouse Protein BTG2