Role of TGF ß1 protein family members (TSC22D) in the control of cell proliferation/differentiation and apoptosis

The TSC22D (TGF ß1-stimulated clone 22 domain) protein family, including TSC22D1 and TSC22D4, play pivotal roles in cell proliferation, differentiation and apoptosis. TSC22D genes encode a large variety of forms arising from alternative splicing and/or post-translational modifications and having synergistic or antagonistic activities. Functional activities of mammalian TSC22D proteins have mostly focused on TSC22D1, encoding a long (TSC22D1.1) and short (TSC22D1.2) splice variants. The antagonistic activities of TSC22D1 isoforms rely on their ability to compete with each other for heterodimerization with TSC22D4. Both TSC22D1 and TSC22D4 are expressed in mouse brain (embryonal/postnatal cerebellum and areas of adult neurogenesis) and in in vitro cerebellar granule neurons (CGNs). We are investigating the specific function(s) played by the various TSC22D forms/isoforms. To this aim, we are exploiting a gene-specific silencing approach by RNA interference. A medulloblastoma cell line, arising from CGN tumors is used as model system to study the role TSC22D family members exert on cell proliferation. In these cells, the silencing of TSC22D4 leads to cell cycle arrest in G0/G1, while that of TSC22D1-1/D1-2 increases the fraction of cells undergoing apoptosis. A similar approach is used in in vitro cultured CGNS, which represent a model to study “differentiation” if cultured in depolarizing condition or “apoptosis” if treated with staurosporine. Overall, TSC22D1.1/ D1.2 display a positive effect on CGN proliferation/differentiation, while TSC22D4 is crucial during early stages of apoptosis. We conclude that TGF ß1 family members have opposite effects and play a key role in the switch proliferation/differentiation and apoptosis.