PC3/Tis21/BTG2 and BTG1 genes: regulators of the cell cycle and neurogenesis, as well as tumor suppressors in malignant brain tumors

: PC3/Tis21/BTG2 and BTG1, prototype members of the BTG/Tob family, are antiproliferative transcriptional cofactors discovered 35 years ago as genes induced by nerve growth factor and phorbol 12-myristate 13-acetate or associated with lymphocytic leukemia. They are today known to serve as developmental regulators in several tissues, including neural cells. Biological functions such as cell division, transcriptional control, DNA repair, and mRNA stability, have been linked to their protein products. We will focus in this review on the effects of PC3/Tis21/BTG2 and BTG1 on brain tumorigenesis and neural development, and on cell cycle and apoptosis. In fact, these genes act as tumor suppressors, and their ability to control tumorigenesis in medulloblastoma and glioma is intrinsically linked to their ability to control the differentiation and proliferation of neural stem and progenitor cells during neurogenesis. Chief function of PC3/Tis21/BTG2 during pre/postnatal and adult neurogenesis is its requirement for the differentiation and migration of neural progenitor cells, in adult hippocampus and subventricular zone-which are the main neurogenic niches where adult neurogenesis occurs-as well as in postnatal cerebellum. Moreover, PC3/Tis21/BTG2 inhibits medulloblastoma onset by promoting the migration and differentiation of cerebellar precursor cells outside the external granular layer, i.e., the proliferative epithelium of the cerebellum, thus diminishing their susceptibility to oncogenic transformation under the influence of Sonic Hedgehog. BTG1, by contrast, primarily functions in neurogenesis to inhibit the proliferation of neural stem and progenitor cells, thereby ensuring the preservation of the cell pool and maintaining the quiescence of medulloblastoma cancer stem cells-known for their persistence against treatments and involvement in tumor relapses-thus preventing their entry in cycle. Furthermore, in glioma, PC3/Tis21/BTG2 enhances apoptosis rates while simultaneously decreasing the migration and invasion of cancerous cells, and lowering the levels of cyclin D1. Similarly, BTG1 contributes to the growth arrest of glioma cells through the regulation of cyclin D1 and p21 expression. PC3/Tis21/BTG2 and BTG1 bind and regulate multiple genes, including Id3, cyclin D1, PRMT1 and the chemokine Cxcl3. These interactions underscore the potential of these cofactors in controlling neurogenesis and tumorigenesis through multiple molecular pathways.