Abstract
Cell cycle regulation is critical for maintenance of genome integrity. A prominent factor that guarantees genomic stability of cells is p53 (ref. 1). The P53 gene encodes a transcription factor that has a role as a tumour suppressor2. Identification of p53-target genes should provide greater insight into the molecular mechanisms that mediate the tumour suppressor activities of p53. The rodent Pc3/Tis21 gene was initially described as an immediate early gene induced by tumour promoters and growth factors in PC12 and Swiss 3T3 cells3,4. It is expressed in a variety of cell and tissue types and encodes a remarkably labile protein4,5. Pc3/Tis21 has a strong sequence similarity to the human antiproliferative BTG1 gene cloned from a chromosomal transloca-tion of a B-cell chronic lymphocytic leukaemia6. This similarity led us to speculate that BTG1 and the putative human homologue of Pc3/Tis21 (named BTG2) were members of a new family of genes involved in growth control and/or differentiation. This hypothesis was recently strengthened by the identification of a new antiproliferative protein, named TOB, which shares sequence similarity with BTG1 and PC3/TIS21 (ref. 7). Here, we cloned and localized the human BTG2 gene. We show that BTG2 expression is induced through a p53-depen-dent mechanism and that BTG2 function may be relevant to cell cycle control and cellular response to DNA damage.
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References
Lane, D.P. P53, guardian of the genome. Nature (London) 358, 15–16 (1992).
Michalowitz, D., Halevy, O. & Oren, M. Conditional inhibition of transformation and cell proliferation by a temperature-sensitive mutant of p53. Cell 62, 671–680 (1990).
Bradbury, A., Possenti, R., Shooter, E.M. & Tirone, F. Molecular cloning of PCS, a putatively secreted protein whose mRNA is induced by nerve growth factor and depolarization. Proc. Natl. Acad. Sci. USA 88, 3353–3357 (1991).
Fletcher, B.S. et al. Structure and expression of TIS21, a primary response gene induced by growth factors and tumor promoters. J. Biol. Chem. 266, 14511–14518 (1991).
Varnum, B.C., Reddy, S.T., Koski, R.A. & Herschman, H.R. Synthesis, degradation, and subcellular localization of proteins encoded by the primary response genes TIS7/PC4 and TIS21/PC3. J. Cell. Physiol. 158, 205–213 (1994).
Rouault, J.P. et al BTG1, a member of a new family of antiproliferative genes. EMBO J. 11, 1663–1670 (1992).
Matsuda, A. et al. Tob, a novel protein that interacts with p185erbB2, is associated with antiproliferative activity. Oncogene 12, 705–713 (1996).
Savatier, P., Huang, S., Szekely, L., Wiman, K.G. & Samarut, J. Contrasting patterns of retinoblastoma protein expression in mouse embryonic stem cells and embryonic fibroblasts. Oncogene 9, 809–818 (1994).
Rao, P.N. in Effects of Drugs on the Cell Nucleus. 475–490 (eds Busch, H., Crooke, S.T. & Daskal, Y.) (Academic Press, New York, 1979).
Vogelstein, B. & Kinzler, K.W. p53 function and dysfunction. Cell 70, 523–526 (1992).
Kastan, M.B., Onyekwere, O., Sidransky, D., Vogelstein, B. & Craig, R.W. Participation of p53 protein in the cellular response to DMA damage. Cancer Res. 51, 6304–6311 (1991).
Fields, S. & Jang, S.K. Presence of a potent transcription activating sequence in the p53 protein. Science 249, 1046–1049 (1990).
Raycroft, L., Wu, H. & Lozano, G. Transcriptional activation by wild-type but not transforming mutants of the p53 anti-oncogene. Science 249, 1049–1051 (1990).
Shaw, P. et al. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc. Natl. Acad. Sci. USA 89, 4495–4499 (1992).
El-Deiry, W.S. et al. WAF1, a potential mediator of p53 tumor suppression. Cell 75, 817–825 (1993).
El-Deiry, W.S., Kern, S.E., Pietenpol, J.A., Kinzler, K.W. & Vogelstein, B. Definition of a consensus binding site for p53. Nature Genet. 1, 45–49 (1992).
El-Deiry, W.S. et al. Topological control of P21WAF1/CIP1 expression in normal and neoplastic tissues. Cancer Res. 55, 2910–2919 (1995).
Hartwell, L.H. & Kastan, M.B. Cell cycle control and cancer. Science 266, 1821–1828 (1994).
Weinert, T.A., & Hartwell, L.H. The RAD9 gene controls the cell cycle response to DNA damage in Saccharomyces cerevisiae . Science 241, 317–322 (1988).
Clarke, A.R. et al. Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362, 849–852 (1993).
Wang, X.W. et al. p53 modulation of TFIIH-associated nucleotide excision repair activity. Nature Genet. 10, 188–194 (1995).
Stewart, N., Hicks, G.G., Paraskevas, F. & Mowat, M. Evidence for a second cell cycle block at G2/M by p53. Oncogene 10, 109–116 (1995).
Aloni-Grinstein, R., Schwartz, D. & Rotter, V. Accumulation of wild-type p53 protein upon γ-irradiation induces a G2 arrest-dependent immunoglobulin κ light chain gene expression. EMBO J. 14, 1392–1401 (1995).
Vikhanskaya, F., Erba, E., D'lncalci, M. & Broggini, M. Introduction of wildtype p53 in a human ovarian cancer cell line not expressing endogenous p53. Nucl. Acids Res. 22, 1012–1017 (1994).
Agarwal, M.L., Agarwal, A., Taylor, W.R. & Stark, G.R. p53 controls both the G2/M and the G1 cell cycle checkpoints and mediates reversible growth arrest in human fibroblasts. Proc. Natl. Acad. Sci. USA 92, 8493–8497 (1995).
Powell, S.N. et al. Differential sensitivity of p53(−) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res. 55, 1643–1648 (1995).
Deng, C., Zhang, P., Harper, J.W., Elledge, S.J. & Leder, P. Mice lacking p21CIP1/WAF1 undergo normal development, but are defective in G1 checkpoint control. Cell 82, 675–684 (1995).
Waldman, T., Kinzler, K.W. & Vogelstein, B. p21 is necessary for the p53-mediated G1 arrest in human cancer cells. Cancer Res. 55, 5187–5190 (1995).
Brugarolas, J. et al. Radiation-induced cell cycle arrest compromised by p21 deficiency. Nature 377, 552–557 (1995).
Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).
Noda, A., Ning, Y., Venable, S.F., Pereira-Smith, O.M. & Smith, J.R. Cloning of senescent cell-derived inhibitors of DMA synthesis using an expression screen. Exp. Cell Res. 211, 90–98 (1994).
Hensler, P.J., Annab, L.A., Barrett, J.C & Pereira-Smith, O.M. A gene involved in control of human cellular senescence on human chromosome 1q. Mol. Cell. Biol. 14, 291–2297 (1994).
Paraskeva, C., Finerty, S. & Powell, S. Immortalization of a human colorectal adenoma cell line by continuous in vitro passage: possible involvement of chromosome 1 in tumour progression. Int. J. Cancer 41, 908–912 (1988).
Mathew, C.G. et al. Deletion of genes on chromosome 1 in endocrine neoplasia. Nature 328, 524–526 (1987).
Chen, L.-C., Dollbaum, C. & Smith, H.S. Loss of heterozygosity on chromosome 1q in human breast cancer. Proc. Natl. Acad. Sci. USA 86, 7204–7207 (1989).
Cherif, D. et al. Simultaneous localization of cosmids and chromosome R-banding by fluorescence microscopy: application to regional mapping of human chromosome 11. Proc. Natl. Acad. Sci. USA 87, 6639–6643 (1990).
Frebourg, T. et al. A functional screen for germ-line p53 mutations based on transcriptional activation. Cancer Res. 52, 6976–6978 (1992).
Baker, S.J., Markowitz, S., Fearon, E.R., Wilson, J.K.W. & Vogelstein, B. Suppression of human colorectal carcinoma cell growth by wild-type p53. Science 249, 912–915 (1990).
Miyashita, T., Harigai, M., Hanada, M. & Reed, J.C. Identification of a p53-dependent negative response element in the bcl-2 gene. Cancer Res. 54, 3131–3135 (1994).
Takahashi, K., Sumimoto, H., Suzuki, K. & Ono, T. Protein-synthesis-dependent cytoplasmic translocation of p53 protein after serum stimulation of growth arrested MCF-7 cells. Mol. Carcinog. 8, 58–66 (1993).
Casey, G., Lo-Hsueh, M., Lopez, M.E., Vogelstein, B. & Stanbridge, E.J. Growth suppression of human breast cancer cells by the introduction of a wild-type p53 gene. Oncogene 6, 1791–1797 (1991).
Puisieux, A. et al. Retinoblastoma and p53 tumor suppressor genes in human hepatoma cell lines. FASEB J. 7, 1407–1413 (1993).
Bartek, J., Iggo, R., Gannon, J. & Lane, D.P. Genetic and immunohistochemical analysis of mutant p53 in human breast cancer cell lines. Oncogene 5, 893–899 (1990).
Bressac, B. et al. Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. Proc. Natl. Acad. Sci. USA 87, 1973–1977 (1990).
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Rouault, JP., Falette, N., Guéhenneux, F. et al. Identification of BTG2, an antiproliferative p53–dependent component of the DNA damage cellular response pathway. Nat Genet 14, 482–486 (1996). https://doi.org/10.1038/ng1296-482
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DOI: https://doi.org/10.1038/ng1296-482
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