Transducer of ERBB2.1 (TOB1) is a
tumor-suppressor protein, which functions as a negative regulator of the
receptor tyrosine-kinase ERBB2. As most of the other
tumor suppressor proteins, TOB1 is inactivated in many human
cancers. Homozygous deletion of TOB1 in mice is reported to be responsible for
cancer development in the lung, liver, and lymph node, whereas the ectopic overexpression of TOB1 shows anti-proliferation, and a decrease in the migration and invasion abilities on
cancer cells. Biochemical studies revealed that the anti-proliferative activity of TOB1 involves
mRNA deadenylation and is associated with the reduction of both
cyclin D1 and
cyclin-dependent kinase (CDK) expressions and the induction of CDK inhibitors. Moreover, TOB1 interacts with an oncogenic signaling mediator, β-
catenin, and inhibits β-
catenin-regulated gene transcription. TOB1 antagonizes the v-akt murine
thymoma viral oncogene (AKT) signaling and induces
cancer cell apoptosis by activating BCL2-associated X (
BAX) protein and inhibiting the BCL-2 and BCL-XL expressions. The
tumor-specific overexpression of TOB1 results in the activation of other
tumor suppressor proteins, such as
mothers against decapentaplegic homolog 4 (SMAD4) and
phosphatase and
tensin homolog-10 (PTEN), and blocks
tumor progression. TOB1-overexpressing
cancer cells have limited potential of growing as xenograft
tumors in nude mice upon subcutaneous implantation. This review addresses the molecular basis of TOB1
tumor suppressor function with special emphasis on its regulation of intracellular signaling pathways.