Antagonistic TSC22D1 variants control BRAFE600-induced senescence

Based on their original genome-wide transcriptome analysis of oncogenic BRAF, Peeper et al report here on TGFβ-stimulated clone 22 (TSC22) transcripts as novel mediator of oncogene-induced senescence triggered by TGFβ, oncogenic RAS and BRAF. The TSC22D1 transcript acts downstream of CEBP/β in the control of senescence-associated pro-inflammatory cytokine and p15INK4b expression

TSC-22D1 isoforms have opposing roles in mammary epithelial cell survival

Transforming growth factor β (TGFβ)-stimulated clone-22 domain family member 1 (TSC-22D1) has previously been associated with enhanced apoptosis in several cell systems. In an attempt to identify novel factors that are involved in the control of cell death during mammary gland involution, we found that the mRNA for isoform 2 of TSC-22D1 was highly upregulated 24 h after forced weaning, when a dramatic increase in cell death occurred, closely following the expression of the known inducer of cell death during involution, TGFβ3. This was paralleled by strongly increased TSC-22D1 isoform 2 protein levels in the luminal epithelium. In contrast, RNA and protein expression levels of the isoform 1 of TSC-22D1 did not change during development. Whereas isoform 2 induced cell death, isoform 1 suppressed TGFβ-induced cell death and enhanced proliferation in mammary epithelial cell lines. Furthermore, four distinct forms of isoform 2 protein were detected in the mammary gland, of which only a 15-kDa form was associated with early involution. Our data describe novel opposing functions of the two mammalian TSC-22D1 isoforms in cell survival and proliferation, and establish the TSC-22D1 isoform 2 as a potential regulator of cell death during mammary gland involution