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

• Published in: Cell death and differentiation Vol. 17; no. 2; pp. 304 - 315
• Main Authors: Huser, C A, Pringle, M A, Heath, V J, Bell, A K, Kendrick, H, Smalley, M J, Crighton, D, Ryan, K M, Gusterson, B A, Stein, T
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.02.2010
• Subjects: Animals; Apoptosis; Apoptosis - physiology; Breastfeeding & lactation; Cancer research; Cell cycle; Cell death; Cell Division - physiology; Cell Survival - physiology; Cloning; Epithelial Cells - cytology; Epithelial Cells - metabolism; Female; Gene Expression - drug effects; Gene Expression - physiology; Growth factors; Isomerism; Mammary Glands, Animal - cytology; Mammary Glands, Animal - physiology; Medical research; Mice; Mice, Inbred Strains; Oligonucleotide Array Sequence Analysis; Pregnancy; Proteins; Repressor Proteins - chemistry; Repressor Proteins - genetics; Repressor Proteins - metabolism; Transcription factors; Transfection; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor beta1 - pharmacology; Transforming Growth Factor beta3 - metabolism; Transforming Growth Factor beta3 - pharmacology; Weaning; United Kingdom > UK
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2009.126

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.