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Tob

[transducer of erbB2] called also Tob1 ([transducer of erbB2 1] approved gene symbol). This 45 kDa protein has been identified by virtue of its ability to interact with the neu oncogene protein (Matsuda et al, 1996). Tob does not contain either SH2 or SH3 domains (see: scr homology domains) but is homologous to the antiproliferative gene product BTG1 at its amino-terminal half. Tob is a member of the BTG family of antiproliferative proteins. Related proteins are AmphiTob and Tob2.

Exogenously expressed Tob is able to suppress growth of NIH 3T3 cells. Tob has been shown also to negatively regulate the proliferation of osteoblasts and T-cells. Gebauer et al (2005) have reported the repression of Tob expression in osteoarthritic cartilage chondrocytes.

Tob activities involve and depend on shuttling between cytoplasmic and nucleocytoplasmic locations (Maekawa et al, 2004; Kawamura-Tsuzuku et al, 2004).

Phosphorylation of Tob by mitogen-activated protein kinases negatively regulates its anti-proliferative functions (Maekawa et al, 2002). Iwanaga et al (2003) have observed a decreased expression of Tob in a very high percentage of lung cancer tissues, but not in normal alveolar epithelial cells. Decreases in Tob expression or the accumulation of phosphorylated Tob are observed in early clinical stages (premalignant dysplasia), suggesting a participation of Tob in the early stage of lung carcinogenesis. Ito et al (2005) have reported that phosphorylation and inactivation of Tob contributes to the progression of papillary carcinoma of the thyroid.

Tzachanis et al (2001) have reported that Tob is highly expressed in anergic T-cell clones, in unstimulated peripheral blood T-lymphocytes, and downregulated during cell activation. Forced expression of Tob inhibits T-cell proliferation and transcription of cytokines and cyclins. Overexpression of Tob suppresses transcription of IL2 through its interaction with SMAD proteins. Okochi et al (2005) have reported that Tob is involved also in the translational suppression of IL2 mRNA in anergic T-cells through interactions with poly(A)-binding proteins. Suppression of Tob, on the other hand, augments responses mediated by CD3 and abrogates the requirement of costimulation for maximal proliferation and cytokine secretion. Thus, T-cell quiescence is an actively maintained phenotype that must be suppressed for T-cell activation to occur.

Yoshida et al (2000) have shown that knock-out mice lacking expression of Tob have a greater bone mass resulting from increased numbers of osteoblasts. Orthotopic bone formation in response to BMP2 is elevated in these mice. Overproduction of Tob represses BMP2 induced transcriptional activation mediated by SMAD proteins. Tob is a negative regulator of BMP and SMAD signaling in osteoblasts and thus negatively regulates osteoblast proliferation and differentiation. Yoshida et al (2003) have reported that Tob represses endogenous BMP signaling by enhancing the interaction between the inhibitory SMAD6 protein and activated BMP type 1 receptors. Yoshida et al (2003) have reported that knock-out mice lacking Tob are predisposed to cancer and that levels of tob mRNA are often decreased in human cancers, implicating tob in cancer development. Usui et al (2004) have reported that Tob deficiency prevents ovariectomy-induced bone loss through the superenhancement of the activities of osteoblasts

Jin et al (2005) have identified Tob as a brain-expressed protein involved in hippocampus-dependent memory consolidation. In the central nervous system Tob is engaged in acquisition of motor skill (Wang et al, 2006).


Copyright 2012 by H IBELGAUFTS. All rights reserved.
ENTRY LAST MODIFIED: June 2006



 

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