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The mammalian target of rapamycin signaling pathway in bovine mammary epithelial cells

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Title: The mammalian target of rapamycin signaling pathway in bovine mammary epithelial cells
Author: Burgos, Sergio A.
Department: Department of Animal and Poultry Science
Advisor: Cant, John P.
Abstract: The molecular mechanisms by which nutritional and endocrine factors affect protein synthesis in the bovine mammary gland are not well understood. The overall objective of the studies presented herein was to determine the role of the mammalian target of rapamycin (mTOR) signaling pathway in the regulation of protein synthesis by nutrients and hormones in bovine mammary epithelial cells (MEC). Mammary epithelial acini isolated from lactating dairy cows were treated in medium containing, either alone or in combination, a mixture of amino acids (AA), glucose and acetate (GA), or a combination of the lactogenic hormones hydrocortisone, insulin and prolactin (HIP). Global protein synthesis in mammary acini was 50% higher with increased availability of AA in medium. The presence of GA or treatment of mammary acini with HIP alone did not affect protein synthesis. The changes in protein synthesis in response to nutrients and hormones were associated changes in the phosphorylation state of ribosomal protein S6 kinase-1 (S6K1) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1). The molecular mechanisms by which cellular energy status and insulin-like growth factor (IGF)-I regulate global protein synthesis through the mTOR signaling pathway were characterized in the bovine MEC line MAC-T. Cellular energy was depleted with the glycolytic inhibitor 2-deoxy-D-g1ucose. Global rates of protein synthesis were reduced by 78% of control values in response to energy depletion. The decline in protein synthesis was associated with reduced phosphorylation of S6K1 and 4E-BP1. There was a marked increase in Ser792 phosphorylation on the regulatory-associated protein of TOR. Global rates of protein synthesis increased by 47% within 30 min of IGF-I treatment. There was a progressive increase in the phosphorylation of S6K1 in response to IGF-I. Activation of Akt by IGF-I led to increased phosphorylation of tuberous sclerosis complex 2 on Thr1426 and pro-rich Akt substrate of 40-kDa at Thr246. Overall, these results suggest that nutrients, cellular energy status and endocrine signals regulate protein synthesis in bovine MEC through changes in the phosphorylation and association state of components of the mTOR signaling pathway.
Date: 2009
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