Disease relevance of Tob1

• In contrast, the ovariectomy-induced increase in the bone resorption parameters, osteoclast surface, and osteoclast number was similar between Tob-deficient mice and WT mice [1].
• Tob (transducer of erbB2) is a member of antiproliferative family proteins and acts as a bone morphogenic protein inhibitor as well as a suppressor of proliferation in T cells, which have been implicated in postmenopausal bone loss [1].

High impact information on Tob1

• Negative regulation of BMP/Smad signaling by Tob in osteoblasts [2].
• Overproduction of Tob represses BMP2-induced, Smad-mediated transcriptional activation [2].
• Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation [3].
• Wild-type Tob inhibits cell growth when the three serine residues are not phosphorylated but is less inhibitory when the serines are phosphorylated [3].
• Oncogenic Ras-induced transformation and growth-factor-induced cell proliferation are efficiently suppressed by mutant Tob that carries alanines but not glutamates, mimicking phosphoserines, at these sites [3].

Biological context of Tob1

• Additionally, Tob contains a nuclear export signal (NES) [4].
• In particular, we evaluated tumor suppressor gene Tob1 for its Par1 candidacy [5].
• Luciferase assay using promoters carrying hormone-responsive elements revealed that both Tob1 and Tob2 proteins but not PC3 suppressed steroid hormone receptor-dependent transcriptional activation in MC3T3-E1 osteoblastic cells [6].
• Bone formation parameters (mineral apposition rate and bone formation rate) in the ovariectomized Tob-deficient mice were significantly higher than those in the ovariectomized WT mice [1].
• Both Tob and estrogen signalings converge at bone morphogenic protein activation of alkaline phosphatase and GCCG-reporter gene expression in osteoblasts, revealing interaction between the two signals [1].

Anatomical context of Tob1

• Tob1 was stabilized in both Skp2(-/-) mouse fibroblasts and Skp2 knockdown HeLa cells [7].
• Furthermore, in ex vivo nodule formation assay, ovariectomy-induced enhancement of nodule formation was significantly higher in the bone marrow cells from Tob-deficient mice than in the bone marrow cells from ovariectomized WT mice [1].

Associations of Tob1 with chemical compounds

• Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1 [7].
• By observation of androgen receptor (AR)-tagged with green fluorescent protein under a confocal laser scanning microscope, we found that Tob1 inhibits the nuclear foci formation of dihydrotestosterone-bound AR [6].
• Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis [1].
• The carboxyl-terminal half of Tob is characterized by the presence of a sequence rich in proline and glutamine and shows no homology to known proteins [8].
• Like human Tob, mouse Tob is characterized by the presence of a sequence rich in proline and glutamine which is often present in the sequence of transcription factors [9].

Physical interactions of Tob1

• The human Tob protein was identified as a molecule that interacted with the ErbB-2 protein, a receptor-type protein tyrosine kinase (RPTK) [9].

Other interactions of Tob1

• In oncogenic ErbB2-transformed cells, nuclear export of Tob is facilitated by NES-mediated mechanism, resulting in decrease of its antiproliferative activity [4].
• Nucleotide sequencing reveals that the Tob protein is a 45 kDa protein that does not contain either SH2 (Src Homology 2) or SH3 domain but is homologous to the previously characterized anti-proliferative gene product BTG-1 at its amino-terminal half [8].

Analytical, diagnostic and therapeutic context of Tob1

• In Tob-deficient mice, ovariectomy reduced bone volume and BMD [1].

References