Abstract
The basic leucine zipper containing activating transcription factors (ATFs) modulates the expression of growth-regulating genes. In this study, we sought to determine specifically the consequences of ATF4 expression on mammary gland development in transgenic mice. Overexpression of ATF4 severely impaired normal development of the mammary gland, which was associated with reduced proliferation and differentiation of mammary alveolar epithelium and up-regulation of p21(WAF1) and p27(Kip1). In addition, there was also impaired lactation accompanied by decreased expression of alpha-lactoalbumin, whey acidic protein, and beta-casein, possibly because of the down-regulation of STAT5a tyrosine phosphorylation. Mammary gland involution in ATF4-transgenic mice was accelerated, compared with wild type littermates by whole mount analysis. In addition, day 18 of lactation in transgenic mice was phenotypically equivalent to day 3 of involution in wild type mice, as determined by the TUNEL assay and expression of Bax. The concentration of the proapoptotic molecule caspase-3 was increased during lactation in ATF4-transgenic animal. Mammary glands from ATF4-transgenic mice also showed significant nuclear translocation of activated STAT3 and up-regulation of one of its target genes, insulin-like growth factor-binding protein-5, which is thought to facilitate apoptosis by sequestering insulin-like growth factor. Together, these findings suggest that ATF4 may play a role during mammary gland development and that down-regulation of ATF4 may be important for the onset of involution in the mammary gland.
Highlights
Among the main regulatory elements that contribute to transcriptional regulation of extracellular signals are the cAMPresponsive element (CRE)1 and activation protein (AP-1) se
Mammary glands from ATF4-transgenic mice showed significant nuclear translocation of activated STAT3 and up-regulation of one of its target genes, insulin-like growth factor-binding protein-5, which is thought to facilitate apoptosis by sequestering insulin-like growth factor. These findings suggest that ATF4 may play a role during mammary gland development and that down-regulation of ATF4 may be important for the onset of involution in the mammary gland
ATF4 Expression and Activity during Mammary Gland Development—To investigate whether ATF4 has any role in normal mammary gland development, we first examined the level of ATF4 and ATF2 protein in wild type mammary glands using Western blot analysis
Summary
Among the main regulatory elements that contribute to transcriptional regulation of extracellular signals are the cAMPresponsive element (CRE) and activation protein (AP-1) se-. ATF4-knockout mice display abnormal lens formation [21, 22] that is at least partially the result of p53-mediated apoptosis because deletion of the p53 gene in the ATF4-knockout background reduces the apoptotic phenotype allowing normal lens formation [21]. The potential role of ATF4 in mammary gland development remains unknown. We have shown previously that heregulin, a mesenchymal growth factor in the mammary gland, up-regulates the expression and transactivation function of ATF4 in breast cancer cells [14]. We showed that overexpression of ATF4 in the mammary epithelium of ATF4-transgenic mice decreased proliferation and impaired differentiation of alveolar epithelial cells during pregnancy and lactation. ATF4 overexpression induced apoptosis and accelerated involution of the mammary gland, suggesting a role for ATF4 in the regulation of normal mammary gland involution
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