Division of Cancer Sciences and Molecular Pathology, University of Glasgow, Glasgow, UK.
Cell Death Differ. 2010 Feb;17(2):304-15. doi: 10.1038/cdd.2009.126. Epub 2009 Sep 11.
Transforming growth factor beta (TGFbeta)-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, TGFbeta3. 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 TGFbeta-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.
转化生长因子β（TGFβ）刺激克隆 22 结构域家族成员 1（TSC-22D1）先前与几种细胞系统中增强的细胞凋亡有关。为了鉴定参与乳腺退化过程中细胞死亡控制的新因子，我们发现 TSC-22D1 同种型 2 的 mRNA 在强制断奶后 24 小时高度上调，此时细胞死亡急剧增加，紧随已知诱导细胞死亡的 TGFβ3 的表达。这与腔上皮细胞中 TSC-22D1 同种型 2 蛋白水平的强烈增加相平行。相比之下，在发育过程中 TSC-22D1 同种型 1 的 RNA 和蛋白表达水平没有变化。虽然同种型 2 诱导细胞死亡，但同种型 1 抑制 TGFβ诱导的细胞死亡并增强乳腺上皮细胞系的增殖。此外，在乳腺中检测到四种不同形式的同种型 2 蛋白，其中只有 15kDa 形式与早期退化有关。我们的数据描述了两种哺乳动物 TSC-22D1 同种型在细胞存活和增殖中的新的相反功能，并确立 TSC-22D1 同种型 2 是乳腺退化过程中细胞死亡的潜在调节剂。
