1. Gene Aliases

BTG Anti-Proliferation Factor 2, PC3, NGF-Inducible Anti-Proliferative Protein PC3, BTG Family Member 2, TIS21, APRO1, Nerve Growth Factor-Inducible Anti-Proliferative, B-Cell Translocation Gene 2, Pheochromacytoma Cell-3, Protein BTG2, MGC126063, MGC126064, BTG Family, Member 2

[https://www.genecards.org/cgi-bin/carddisp.pl?gene=BTG2&keywords=Btg2]

2. Association with Toxicity and/or Disease at a Transcriptional Level

3. Summary of Protein Family and Structure

4. Proteins Known to Interact with Gene Product

Interactions with experimental support

5. Links to Gene Databases

6. GO Terms, MSigDB Signatures, Pathways Containing Gene with Descriptions of Gene Sets

Pathways:

RNA Polymerase II Transcription: RNA polymerase II (Pol II) is the central enzyme that catalyses DNA- directed mRNA synthesis during the transcription of protein-coding genes. Pol II consists of a 10-subunit catalytic core, which alone is capable of elongating the RNA transcript, and a complex of two subunits, Rpb4/7, that is required for transcription initiation.

The transcription cycle is divided in three major phases: initiation, elongation, and termination. Transcription initiation include promoter DNA binding, DNA melting, and initial synthesis of short RNA transcripts. The transition from initiation to elongation, is referred to as promoter escape and leads to a stable elongation complex that is characterized by an open DNA region or transcription bubble. The bubble contains the DNA-RNA hybrid, a heteroduplex of eight to nine base pairs. The growing 3-end of the RNA is engaged with the polymerase complex active site. Ultimately transcription terminates and Pol II dissocitates from the template. [https://reactome.org/PathwayBrowser/#/R-HSA-73857]

TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain: BTG2 is induced by TP53, leading to cessation of cellular proliferation (Rouault et al. 1996, Duriez et al. 2002). BTG2 binds to the CCR4-NOT complex and promotes mRNA deadenylation activity of this complex. Interaction between BTG2 and CCR4-NOT is needed for the antiproliferative activity of BTG2, but the underlying mechanism has not been elucidated (Rouault et al. 1998, Mauxion et al. 2008, Horiuchi et al. 2009, Doidge et al. 2012, Ezzeddine et al. 2012). Two polo-like kinases, PLK2 and PLK3, are direct transcriptional targets of TP53. TP53-mediated induction of PLK2 may be important for prevention of mitotic catastrophe after spindle damage (Burns et al. 2003). PLK2 is involved in the regulation of centrosome duplication through phosphorylation of centrosome-related proteins CENPJ (Chang et al. 2010) and NPM1 (Krause and Hoffmann 2010). PLK2 is frequently transcriptionally silenced through promoter methylation in B-cell malignancies (Syed et al. 2006). Induction of PLK3 transcription by TP53 (Jen and Cheung 2005) may be important for coordination of M phase events through PLK3-mediated nuclear accumulation of CDC25C (Bahassi et al. 2004). RGCC is induced by TP53 and implicated in cell cycle regulation, possibly through its association with PLK1 (Saigusa et al. 2007). PLAGL1 (ZAC1) is a zinc finger protein directly transcriptionally induced by TP53 (Rozenfeld-Granot et al. 2002). PLAGL1 expression is frequently lost in cancer (Varrault et al. 1998) and PLAGL1 has been implicated in both cell cycle arrest and apoptosis (Spengler et al. 1997), but its mechanism of action remains unknown. [https://reactome.org/PathwayBrowser/#/R-HSA-6804115]

GO terms:

DNA damage response [Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating damage to its DNA from environmental insults or errors during metabolism. GO:0006974]

anterior/posterior pattern specification [The regionalization process in which specific areas of cell differentiation are determined along the anterior-posterior axis. The anterior-posterior axis is defined by a line that runs from the head or mouth of an organism to the tail or opposite end of the organism. GO:0009952]

associative learning [Learning by associating a stimulus (the cause) with a particular outcome (the effect). GO:0008306]

central nervous system neuron development [The process whose specific outcome is the progression of a neuron whose cell body is located in the central nervous system, from initial commitment of the cell to a neuronal fate, to the fully functional differentiated neuron. GO:0021954]

dentate gyrus development [The process whose specific outcome is the progression of the dentate gyrus over time, from its formation to the mature structure. The dentate gyrus is one of two interlocking gyri of the hippocampus. It contains granule cells, which project to the pyramidal cells and interneurons of the CA3 region of the ammon gyrus. GO:0021542]

negative regulation of apoptotic process [Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process.|This term should only be used when it is not possible to determine which phase or subtype of the apoptotic process is negatively regulated by a gene product. Whenever detailed information is available, the more granular children terms should be used. GO:0043066]

negative regulation of cell population proliferation [Any process that stops, prevents or reduces the rate or extent of cell proliferation. GO:0008285]

negative regulation of mitotic cell cycle [Any process that stops, prevents or reduces the rate or extent of progression through the mitotic cell cycle. GO:0045930]

negative regulation of neuroblast proliferation [Any process that stops, prevents, or reduces the frequency, rate or extent of the proliferation of neuroblasts. GO:0007406]

negative regulation of neuron apoptotic process [Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process in neurons. GO:0043524]

negative regulation of transcription by RNA polymerase II [Any process that stops, prevents, or reduces the frequency, rate or extent of transcription mediated by RNA polymerase II. GO:0000122]

negative regulation of translation [Any process that stops, prevents, or reduces the frequency, rate or extent of the chemical reactions and pathways resulting in the formation of proteins by the translation of mRNA or circRNA. GO:0017148]

neural precursor cell proliferation [The multiplication or reproduction of neural precursor cells, resulting in the expansion of a cell population. A neural precursor cell is either a nervous system stem cell or a nervous system progenitor cell. GO:0061351]

neuroblast proliferation [The expansion of a neuroblast population by cell division. A neuroblast is any cell that will divide and give rise to a neuron. GO:0007405]

neuron differentiation [The process in which a relatively unspecialized cell acquires specialized features of a neuron. GO:0030182]

neuron projection development [The process whose specific outcome is the progression of a neuron projection over time, from its formation to the mature structure. A neuron projection is any process extending from a neural cell, such as axons or dendrites (collectively called neurites). GO:0031175]

positive regulation of nuclear-transcribed mRNA poly(A) tail shortening [Any process that increases the frequency, rate or extent of poly(A) tail shortening of a nuclear-transcribed mRNA. Poly(A) tail shortening is the decrease in length of the poly(A) tail of an mRNA from full length to an oligo(A) length. GO:0060213]

response to electrical stimulus [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an electrical stimulus. GO:0051602]

response to mechanical stimulus [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a mechanical stimulus. GO:0009612]

response to organic cyclic compound [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an organic cyclic compound stimulus. GO:0014070]

response to organic substance [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an organic substance stimulus. GO:0010033]

response to organonitrogen compound [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of an organonitrogen stimulus. An organonitrogen compound is formally a compound containing at least one carbon-nitrogen bond. GO:0010243]

response to peptide hormone [Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a peptide hormone stimulus. A peptide hormone is any of a class of peptides that are secreted into the blood stream and have endocrine functions in living animals. GO:0043434]

skeletal muscle cell differentiation [The process in which a relatively unspecialized cell acquires specialized features of a skeletal muscle cell, a somatic cell located in skeletal muscle. GO:0035914]

MSigDB Signatures:

WP_SPINAL_CORD_INJURY: Spinal cord injury [https://www.gsea-msigdb.org/gsea/msigdb/human/geneset/WP_SPINAL_CORD_INJURY.html]

7. Gene Descriptions

NCBI Gene Summary: 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 encoded protein is involved in the regulation of the G1/S transition of the cell cycle. [provided by RefSeq, Jul 2008]

GeneCards Summary: BTG2 (BTG Anti-Proliferation Factor 2) is a Protein Coding gene. Diseases associated with BTG2 include Diffuse Large B-Cell Lymphoma Activated B-Cell Type and Lung Cancer. Among its related pathways are Gene expression (Transcription) and TP53 Regulates Transcription of Cell Cycle Genes. Gene Ontology (GO) annotations related to this gene include DNA-binding transcription activator activity, RNA polymerase II-specific. An important paralog of this gene is BTG1.

UniProtKB/Swiss-Prot Summary: Anti-proliferative protein; the function is mediated by association with deadenylase subunits of the CCR4-NOT complex. Activates mRNA deadenylation in a CNOT6 and CNOT7-dependent manner. In vitro can inhibit deadenylase activity of CNOT7 and CNOT8. Involved in cell cycle regulation. Could be involved in the growth arrest and differentiation of the neuronal precursors. Modulates transcription regulation mediated by ESR1. Involved in mitochondrial depolarization and neurite outgrowth.

8. Cellular Location of Gene Product

Cytoplasmic expression in selected tissues. Mainly localized to vesicles. In addition localized to the nucleoplasm. Predicted location: Intracellular [https://www.proteinatlas.org/ENSG00000159388/subcellular]

9. Mechanistic Information

Summary

The BTG2 gene, known for its anti-proliferative properties, is significantly downregulated in skin cancer cells [CS: 8]. This downregulation disrupts its normal function in regulating cell cycle progression [CS: 8]. Normally, BTG2 expression leads to decreased levels of beta-catenin, cyclin D1, and v-myc [CS: 7], which are crucial for the Wnt/beta-catenin signaling pathway involved in cell proliferation and migration [CS: 8]. In skin cancer, the lack of BTG2's regulatory action allows uncontrolled cell proliferation and migration, key characteristics of cancerous growths [CS: 8].

In response to skin stress or toxicity, such as in the case of quercetin treatment in melanoma cells, BTG2 expression is differentially modulated [CS: 5]. This modulation suggests a protective response against cellular stress [CS: 5]. By influencing the mRNA deadenylation process and interacting with deadenylase subunits of the CCR4-NOT complex, BTG2 plays a role in controlling mRNA stability and degradation, which is crucial in the rapid adaptation of cells to stress conditions [CS: 6]. Thus, in the context of skin diseases or toxicities, BTG2's modulation can be seen as a cellular attempt to counteract abnormal proliferation and promote cell cycle arrest, maintaining cellular homeostasis [CS: 7].

10. Upstream Regulators

11. Tissues/Cell Type Where Genes are Overexpressed

Tissue type enchanced: low tissue specificity [https://www.proteinatlas.org/ENSG00000159388/tissue]

Cell type enchanced: basal prostatic cells (cell type enhanced) [https://www.proteinatlas.org/ENSG00000159388/single+cell+type]

12. Role of Gene in Other Tissues

13. Chemicals Known to Elicit Transcriptional Response of Biomarker in Tissue of Interest

Compounds that increase expression of the gene:

14. DisGeNet Biomarker Associations to Disease in Organ of Interest

Most relevant biomarkers with lower score or lower probability of association with disease or organ of interest: