The interplay between TGF‐β‐stimulated TSC22 domain family proteins regulates cell‐cycle dynamics in medulloblastoma cells

Proteins belonging to the TGFβ‐stimulated clone 22 domain (TSC22D) family display a repertoire of activities, regulating cell proliferation and differentiation. The tumor suppressor activity of the first identified member of the family, TSC22D1 (formerly named TSC‐22), has been extensively studied, but afterward a longer isoform encoded by the same gene turned out to play an opposite role. We have previously characterized the role of TSC22D1 and TSC22D4 in cell differentiation using granule neurons (GNs) isolated from the mouse cerebellum. However, the possibility to study the role of these factors in cell proliferation was limited by the fact that GNs readily exit from the cell‐cycle and differentiate upon isolation and in vitro culture. To overcome this limitation, we have now exploited DAOY medulloblastoma cells, which are ontogenetically similar to cerebellar GNs and can be efficiently transfected with interfering RNA for gene knockdown purposes. Our findings indicate that TSC22D4–TSC22D1 short isoform heterodimers are involved in the escape from cell proliferation and exit from the cell‐cycle, whereas, the TSC22D1 long isoform is required for cell proliferation, acting independently from TSC22D4. We also show that the silencing of specific expression of TSC22D4 or TSC22D1 isoforms affects the cell‐cycle progression. These findings add a novel insight on the function of TSC22D proteins, with particular reference to the tumor suppressor activity of the TSC22D1 short isoform, which is re‐framed within the context of a functional interplay with TSC22D4 and the mutually exclusive expression with the TSC22D1 long isoform. TSC22 domain family proteins regulate cell survival and cell‐cycle progression. The silencing of specific expression of TSC22D1 long isoform and TSC22D4 results in increased apoptosis and cell‐cycle arrest, respectively.