Alternative titles; symbols
HGNC Approved Gene Symbol: TOB1
Cytogenetic location: 17q21.33 Genomic coordinates (GRCh38): 17:50,862,223-50,867,978 (from NCBI)
Matsuda et al. (1996) cloned a cDNA encoding TOB1, which they called TOB, a protein that interacts with the ERBB2 (164870) gene product p185. Sequence analysis revealed that TOB1 is a 45-kD, 345-amino acid protein whose N-terminal half is homologous to the antiproliferative gene product BTG1 (109580). The C-terminal half of TOB1 is characterized by the presence of a proline- and glutamine-rich sequence. Expression of TOB1 mRNA was observed in various cell types.
Matsuda et al. (1996) found that, like BTG1, exogenously expressed TOB1 was able to suppress growth of NIH 3T3 cells, but the growth suppression was hampered by the presence of kinase-active p185. By using GST-TOB1 proteins containing either full-length TOB1 or the N-terminal half of TOB1, Matsuda et al. (1996) showed that the C-terminal half of TOB1 was relevant to its interaction with p185. Furthermore, TOB1 could be coimmunoprecipitated with anti-ERBB2 antibody, and reciprocally, p185 could be coimmunoprecipitated with anti-TOB1 antibodies. These data suggested that p185 negatively regulates the TOB1-mediated antiproliferative pathway through its interaction with TOB1, resulting possibly in growth stimulation by p185. Expression of TOB1 mRNA was not correlated with expression of ERBB2, suggesting that other receptor-type protein-tyrosine kinases are also involved in the TOB1-mediated regulation of cell growth.
Tzachanis et al. (2001) used antigen-specific T-cell clones rendered anergic by stimulation of T-cell receptor (see 186810) in the absence of costimulation or interleukin-2 (IL2; 147680) and suppression subtractive hybridization and differential screening to identify genes selectively expressed in anergic cells. TOB was constitutively expressed in primary peripheral blood T lymphocytes and had to be downregulated for T-cell activation. Immunoprecipitation, immunoblot, and gel-shift analyses showed that TOB interacts with SMAD4 (MADH4; 600993) and, to a lesser degree, with SMAD2 (601366) and augments SMAD DNA binding to sites in the IL2 promoter, leading to an inhibition of IL2 transcription. Tzachanis et al. (2001) concluded that T-cell quiescence is an actively maintained phenotype that must be suppressed to allow T-cell activation to occur, suggesting targets for the manipulation of the immune response.
Xiong et al. (2006) found that zebrafish Tob1a was required for correct dorsoventral patterning. Tob1a inhibited beta-catenin (CTNNB1; 116806) transcriptional activity by physically associating with beta-catenin and preventing formation of beta-catenin/Lef1 (153245) complexes. Although Tob1a also inhibited the transcriptional activity of Smad3 (603109), its role in limiting dorsal development was executed primarily by antagonizing the beta-catenin signal. By immunoprecipitation analysis, Xiong et al. (2006) showed that endogenous TOB1 and beta-catenin interacted in human HEK293T cells. SMAD3 also immunoprecipitated with TOB1 in human cells.
By FISH, Matsuda et al. (1996) mapped the TOB1 gene to 17q21.
Yoshida et al. (2000) showed that murine Tob is a negative regulator of bone morphogenetic protein (BMP; see 112265)/SMAD signaling in osteoblasts. Mice carrying a targeted deletion of the Tob gene had a greater bone mass due to increased numbers of osteoblasts. Orthotopic bone formation in response to Bmp2 (112261) was elevated in Tob-deficient mice. Overproduction of Tob repressed Bmp2-induced, Smad-mediated transcriptional activation. Tob associated with receptor-regulated Smads, including Smad1 (601595), Smad5 (603110), and Smad8 (603295), and colocalized with these SMADs in the nuclear bodies upon BMP2 stimulation. The results indicated that Tob negatively regulates osteoblast proliferation and differentiation by suppressing the activity of the receptor-regulated Smad proteins.
Schulze-Topphoff et al. (2013) found that the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS; 126200) in Tob1-null mice was associated with augmented central nervous system inflammation, increased Cd4 (186940)-positive and Cd8 (see 186910)-positive T cells, increased myelin-reactive T helper-1 (Th1) and Th17 (see 603149) cells, and reduced numbers of regulatory T cells. Reconstitution of T cell-deficient Rag1 (179615)-null mice with Tob1-null Cd4-positive T cells also resulted in the aggressive EAE phenotype. Schulze-Topphoff et al. (2013) concluded that Tob1 plays a critical role in the adaptive T-cell responses that drive development of demyelinating disease and proposed that TOB1 may be a useful biomarker for demyelinating disease activity.
Matsuda, S., Kawamura-Tsuzuku, J., Ohsugi, M., Yoshida, M., Emi, M., Nakamura, Y., Onda, M., Yoshida, Y., Nishiyama, A., Yamamoto, T. Tob, a novel protein that interacts with p185erbB2, is associated with anti-proliferative activity. Oncogene 12: 705-713, 1996. [PubMed: 8632892]
Schulze-Topphoff, U., Casazza, S., Varrin-Doyer, M., Pekarek, K., Sobel, R. A., Hauser, S. L., Oksenberg, J. R., Zamvil, S. S., Baranzini, S. E. Tob1 plays a critical role in the activation of encephalitogenic T cells in CNS autoimmunity. J. Exp. Med. 210: 1301-1309, 2013. [PubMed: 23797093] [Full Text: https://doi.org/10.1084/jem.20121611]
Tzachanis, D., Freeman, G. J., Hirano, N., van Puijenbroek, A. A. F. L., Delfs, M. W., Berezovskaya, A., Nadler, L. M., Boussiotis, V. A. Tob is a negative regulator of activation that is expressed in anergic and quiescent T cells. Nature Immun. 2: 1174-1182, 2001. [PubMed: 11694881] [Full Text: https://doi.org/10.1038/ni730]
Xiong, B., Rui, Y., Zhang, M., Shi, K., Jia, S., Tian, T., Yin, K., Huang, H., Lin, S., Zhao, X., Chen, Y., Chen, Y.-G., Lin, S.-C., Meng, A. Tob1 controls dorsal development of zebrafish embryos by antagonizing maternal beta-catenin transcriptional activity. Dev. Cell 11: 225-238, 2006. [PubMed: 16890162] [Full Text: https://doi.org/10.1016/j.devcel.2006.06.012]
Yoshida, Y., Tanaka, S., Umemori, H., Minowa, O., Usui, M., Ikematsu, N., Hosoda, E., Imamura, T., Kuno, J., Yamashita, T., Miyazono, K., Noda, M., Noda, T., Yamamoto, T. Negative regulation of BMP/Smad signaling by Tob in osteoblasts. Cell 103: 1085-1097, 2000. [PubMed: 11163184] [Full Text: https://doi.org/10.1016/s0092-8674(00)00211-7]