Alternative titles; symbols
HGNC Approved Gene Symbol: BTG2
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38) : 1:203,305,519-203,309,602 (from NCBI)
BTG2 encodes an antiproliferative protein involved in the regulation of the G1/S transition of the cell cycle (summary by Duriez et al., 2002).
The BTG2 gene was isolated in the rat by Bradbury et al. (1991) as an immediate early gene induced by nerve growth factor (NGF; 162030) in pheochromocytoma cells that undergo neural differentiation in the presence of NGF. The gene was called PC3 for pheochromocytoma cell-3. Its induction was independent of new protein synthesis as it could occur in the presence of cycloheximide. PC3 was also induced with similar kinetics, but at lower levels, by membrane depolarization (both in vivo and in vitro) and epidermal growth factor (131530). Montagnoli et al. (1996) demonstrated that PC3 has antiproliferative activity and is involved in cell cycle regulation.
Rouault et al. (1996) cloned the human BTG2 gene from a lymphoblastoid cell line cDNA library. The sequence predicted a 158-amino acid protein which shares 93.6% identity with the murine Tis21 protein and 66.4% identity with the BTG1 (109580) protein. Rouault et al. (1996) noted that the only significant difference between the BTG1 and BTG2 protein sequences is a 10-amino acid insertion in the C-terminal part of the BTG1 protein.
Rouault et al. (1996) determined that BTG2 was preferentially expressed in quiescent cells and that overexpression of this gene causes a decrease in the growth rate and clonability of NIH 3T3 cells. Btg2 disruption had no detectable effect on the growth of differentiated or undifferentiated embryonic stem (ES) cells. Rouault et al. (1996) reported that Btg2/Tis21 inactivation in ES cells leads to a striking disruption of DNA damage-induced G2/M arrest and to a marked increase in cell death. Rouault et al. (1996) concluded that BTG2 function may be relevant to cell cycle control and to cellular response to DNA damage. They noted that in response to DNA damage, eukaryotic cells delay cell cycle progression from G1 to S and from G2 to M by induction of antiproliferative genes. Arrest in G1 is thought to prevent replication of damaged genetic templates; arrest prior to M allows cells to avoid segregation of defective chromosomes. Rouault et al. (1996) determined that p53 (191170) regulates BTG2 gene expression.
By analyzing genes universally downregulated in cells lacking p53 activity, Boiko et al. (2006) identified BTG2 as a major downstream effector of p53-dependent proliferation arrest in mouse and human fibroblasts transduced with oncogenic Ras (see HRAS; 190020). Short hairpin RNA-mediated knockdown of Btg2 cooperated with oncogenic Ras to transform primary mouse fibroblasts expressing wildtype p53 activity. Repression of Btg2 resulted in upregulation of cyclin D1 (CCND1; 168461) and cyclin E1 (CCNE1; 123837) and phosphorylation of RB (614041) and, in cooperation with other oncogenic elements, induced neoplastic transformation of primary human fibroblasts. BTG2 expression was significantly reduced in a large proportion of human kidney and breast carcinomas, suggesting that BTG2 is a tumor suppressor that links p53 and RB pathways in human tumorigenesis.
Using a short hairpin RNA screen targeting 43 histone lysine methyltransferases (KMTs), Tajima et al. (2015) showed that the KMT SETD1A (611052) suppressed expression of the antiproliferative gene BTG2 by inducing several BTG2-targeting microRNAs. Although the mechanism was indirect, it was a highly specific way by which a chromatin regulator that mediates transcriptional activating marks could induce downregulation of a critical effector gene. Moreover, the mechanism was shared with multiple genes of the p53 pathway. Tajima et al. (2015) concluded that SETD1A has an important role in regulating tumor growth.
Hwang et al. (2020) identified BTG1 (109580) and BTG2 as factors responsible for T-cell quiescence. BTG1/2-deficient T cells show an increased proliferation and spontaneous activation due to a global increase in mRNA abundance, which reduces the threshold to activation. BTG1/2 deficiency leads to an increase in polyadenylate tail length, resulting in a greater mRNA half-life. Thus, BTG1 and BTG2 promote the deadenylation and degradation of mRNA to secure T-cell quiescence. Hwang et al. (2020) concluded that their study revealed a key mechanism underlying T-cell quiescence and suggested that low mRNA abundance is a crucial feature for maintaining quiescence.
Duriez et al. (2002) determined that the BTG2 gene contains 2 exons. They identified several CG-rich regions containing 3 Sp1-binding sites, including 3 SP1 (189906)-binding sites in GC-rich regions, and a major p53 response element.
Rouault et al. (1996) mapped the BTG2 gene to human chromosome 1q32 by fluorescence in situ hybridization and by Southern blot analysis of human somatic cell hybrids.
In a study of cis-suppression of human disease mutations by comparative genomics, Jordan et al. (2015) identified a heterozygous missense mutation (V141M; 601597.0001) in the BTG gene in a patient with microcephaly.
This variant is classified as a variant of unknown significance because its contribution to microcephaly has not been confirmed.
Jordan et al. (2015) identified a 17-month-old female with an undiagnosed neuroanatomic condition hallmarked by microcephaly and performed whole-exome sequencing on this patient, her unaffected parents, and an unaffected sister. In the proband, the authors identified a de novo heterozygous missense mutation, val141-to-met (V141M), that arose from a G-to-A transition at nucleotide 421 of the BTG gene. Knockdown of btg in zebrafish resulted in significant reduction of anterior structures that was rescued with wildtype human BTG2 mRNA. In contrast, injection of mRNA harboring the V141M variant was significantly worse at rescue than wildtype. Suppression of btg led to a decrease of postmitotic neurons as indicated by immunohistochemical staining assays; this defect was rescued by wildtype BTG mRNA as well as by coinjection of 2 rare control alleles, but could not be ameliorated by V141M-encoded mRNA coinjection. Jordan et al. (2015) also showed significant reduction in cell proliferation in the BTG2 morphants that was rescued with wildtype human mRNA.
Boiko, A. D., Porteous, S., Razorenova, O. V., Krivokrysenko, V. I., Williams, B. R., Gudkov, A. V. A systematic search for downstream mediators of tumor suppressor function of p53 reveals a major role of BTG2 in suppression of Ras-induced transformation. Genes Dev. 20: 236-252, 2006. [PubMed: 16418486] [Full Text: https://doi.org/10.1101/gad.1372606]
Bradbury, A., Possenti, R., Shooter, E. M., Tirone, F. Molecular cloning of PC3, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization. Proc. Nat. Acad. Sci. 88: 3353-3357, 1991. [PubMed: 1849653] [Full Text: https://doi.org/10.1073/pnas.88.8.3353]
Duriez, C., Falette, N., Audoynaud, C., Moyret-Lalle, C., Bensaad, K., Courtois, S., Wang, Q., Soussi, T., Puisieux, A. The human BTG2/TIS21/PC3 gene: genomic structure, transcriptional regulation and evaluation as a candidate tumor suppressor gene. Gene 282: 207-214, 2002. [PubMed: 11814693] [Full Text: https://doi.org/10.1016/s0378-1119(01)00825-3]
Hwang, S. S., Lim, J., Yu, Z., Kong, P., Sefik, E., Xu, H., Harman, C. C. D., Kim, L. K., Lee, G. R., Li, H.-B., Flavell, R. A. mRNA destabilization by BTG1 and BTG2 maintains T cell quiescence. Science 367: 1255-1260, 2020. [PubMed: 32165587] [Full Text: https://doi.org/10.1126/science.aax0194]
Jordan, D. M., Frangakis, S. G., Golzio, C., Cassa, C. A., Kurtzberg, J., Task Force for Neonatal Genomics, Davis, E. E., Sunyaev, S. R., Katsanis, N. Identification of cis-suppression of human disease mutations by comparative genomics. Nature 524: 225-229, 2015. [PubMed: 26123021] [Full Text: https://doi.org/10.1038/nature14497]
Montagnoli, A., Guardavaccaro, D., Starace, G., Tirone, F. Overexpression of the nerve growth factor-inducible PC3 immediate early gene is associated with growth inhibition. Cell Growth Differ. 7: 1327-1336, 1996. [PubMed: 8891336]
Rouault, J.-P, Falette, N., Guehenneux, F., Guillot, C., Rimokh, R., Wang, Q., Berthet, C., Moyret-Lalle, C., Savatier, P., Pain, B., Shaw, P., Berger, R., Samarut, J., Magaud, J.-P., Ozturk, M., Samarut, C., Puisieux, A. Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nature Genet. 14: 482-486, 1996. [PubMed: 8944033] [Full Text: https://doi.org/10.1038/ng1296-482]
Tajima, K., Yae, T., Javaid, S., Tam, O., Comaills, V., Morris, R., Wittner, B. S., Liu, M., Engstrom, A., Takahashi, F., Black, J. C., Ramaswamy, S., Shioda, T., Hammell, M., Haber, D. A., Whetstine, J. R., Maheswaran, S. SETD1A modulates cell cycle progression through a miRNA network that regulates p53 target genes. Nature Commun. 6: 8257, 2015. Note: Electronic Article. [PubMed: 26394836] [Full Text: https://doi.org/10.1038/ncomms9257]