The differentiation of mammary epithelial cells into secretory cells capable of sustaining lactation is of great mportance to newborn health. Secretory activation occurs at parturition, marks the transition between late pregnancy and lactation, and is dependent on Akt. Since diseases such as diabetes and obesity are correlated with Aktl activity and adversely effect lactation. Understanding how Akt functions normally during secretory activation will provide the means to understand lactation defects resulting from these disorders. Much of the molecular analysis of events that underlie this transition has focused upon the regulation of milk protein gene expression. However, milk fat provides the crucial nutrient that supports both growth and brain development of the offspring. Akt dependent metabolic changes that occur at secretory activation include increased glucose transport and elevated lipogenesis that maintain a constant fat composition in milk. We hypothesize that Aktl is a critical genetic regulator of secretory activation that is particularly important in the metabolic switch that occurs at this transition.
Three specific aims are designed to test this hypothesis: 1) We will identify genes specific to the mammary epithelium whose expression is regulated by Aktl during secretory differentiation and activation using qPCR and global expression arrays. 2) We will test these Akt dependent regulators for ability to restore lipogenic differentiation and secretory activation in established mammary epithelial cell lines in vitro and in Aktl null mammary epithelium in vivo. We will determine whether any of these genes can stimulate fatty acid biosynthesis to form cytoplasmic lipid droplets in the absence of differentiation stimuli. 3) We will identify mammary epithelium specific phosphorylated protein substrates for Aktl that are necessary for lipogenic differentiation and secretory activation by using multiple proteomic platforms that identify phosphorylated proteins. Cumulatively, the identification of Aktl dependent genes, plus Aktl dependent protein substrates, will allow us to elucidate normal mammary epithelium function of Aktl. We ultimately will provide a strong foundation toward enhancing the impaired lactation of women who are afflicted by diabetes and/or obesity.
Aktl regulates lipogenic differentiation of mammary epithelial cells during pregnancy and lactation;however, it also integrates signals for cell survival, proliferation, and energy metabolism. Because Aktl is activated by diabetes and obesity, it integrates both normal and abnormal stimuli to modulate mammary gland function. Understanding how Akt functions may improve lactation in obese and diabetic women.
|TreviÃ±o, Lindsey S; Bolt, Michael J; Grimm, Sandra L et al. (2016) Differential Regulation of Progesterone Receptor-Mediated Transcription by CDK2 and DNA-PK. Mol Endocrinol 30:158-72|
|Sladek, Celia D; Stevens, Wanida; Song, Zhilin et al. (2016) The "metabolic sensor" function of rat supraoptic oxytocin and vasopressin neurons is attenuated during lactation but not in diet-induced obesity. Am J Physiol Regul Integr Comp Physiol 310:R337-45|
|Heinz, Richard E; Rudolph, Michael C; Ramanathan, Palani et al. (2016) Constitutive expression of microRNA-150 in mammary epithelium suppresses secretory activation and impairs de novo lipogenesis. Development 143:4236-4248|
|Rudolph, Michael C; Young, Bridget E; Jackson, Kristina Harris et al. (2016) Human Milk Fatty Acid Composition: Comparison of Novel Dried Milk Spot Versus Standard Liquid Extraction Methods. J Mammary Gland Biol Neoplasia 21:131-138|
|Wellberg, Elizabeth A; Rudolph, Michael C; Lewis, Andrew S et al. (2014) Modulation of tumor fatty acids, through overexpression or loss of thyroid hormone responsive protein spot 14 is associated with altered growth and metastasis. Breast Cancer Res 16:481|
|Schmidt, Jeffrey W; Wehde, Barbara L; Sakamoto, Kazuhito et al. (2014) Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis. Mol Cell Biol 34:1363-77|
|Rudolph, Michael C; Wellberg, Elizabeth A; Lewis, Andrew S et al. (2014) Thyroid hormone responsive protein Spot14 enhances catalysis of fatty acid synthase in lactating mammary epithelium. J Lipid Res 55:1052-65|
|Pereira, Renata O; Wende, Adam R; Crum, Ashley et al. (2014) Maintaining PGC-1Î± expression following pressure overload-induced cardiac hypertrophy preserves angiogenesis but not contractile or mitochondrial function. FASEB J 28:3691-702|
|McManaman, James L (2014) Lipid transport in the lactating mammary gland. J Mammary Gland Biol Neoplasia 19:35-42|
|Wellberg, Elizabeth A; Anderson, Steven M (2014) FASNating targets of metformin in breast cancer stem-like cells. Horm Cancer 5:358-62|
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