During the peripartum period, the lung must respond to dramatic changes in circulating hormones, nutritional factors, and physiologic signals during its transition to becoming the organ of gas exchange. Protein synthesis consumes a significant proportion of metabolic resources and is inhibited by many environmental stresses. We hypothesized that translational control mechanisms play a role in the perinatal lung. Immunoblots of late-gestation (Fetal Day [FD] 17-22) rat lung extracts revealed gradual decreases in phosphorylated forms of the mammalian target of rapamycin effectors, eukaryotic initiation factor (eIF) 4E-binding protein, p70 S6 kinase, and ribosomal protein S6, followed by sharp increases on Postnatal Day 1 (P1). Immunohistochemistry showed phospho-S6 staining was most prominent in epithelial cells of the large and small airways. m(7)GTP-sepharose pulldown experiments showed a decrease in association of translation initiation factor, eIF4E, with its inhibitor, eIF4E-binding protein, and a concomitant increase in eIF4E association with eIF4G immediately after birth, and polysome profiles confirmed a decrease in abundance of large polysomes between FD19 and FD22, which was reversed on P1. Microarray analysis of polysomal versus total RNA from FD19, FD22, and P1 lungs was used to identify specific genes, the association of which with large polysomes changed either pre- or postnatally. RT-PCR and Northern blotting were used to confirm translational changes in selected candidate genes, including a prenatal increase in IL-18 and a postnatal decrease in regulatory subunit 2 of protein phosphatase 1. Translational regulation of IL-18 and protein phosphatase 1 regulatory (inhibitor) subunit 2 is gene-specific, as these changes contrast with the corresponding global changes in polysome abundance.
"In mice, its expression arises at E8.5 and its inhibition, by mutation or with rapamycin, results in forebrain defects, loss of somites, poor embryonic rotation and lethality by E12.5 (Hentges et al., 2001). Ontogenic studies of mTOR function in rat fetuses show its activity is high during the early stages of development, declining towards term, but rebounds during the early neonatal period and corresponds with proportionate changes in translation efficiency during gestation and birth (Otulakowski et al, 2009; 2007). In fetal lung in vivo, phosphorylation of the mTORC-1 specific substrate, S6 kinase-1 Thr 389 , is high in the epithelium within the airway bud tip and genomic knockout of its upstream repressor, tuberous sclerosis complex-1 (TSC1), leads to gross vascular defects and widespread expression of VEGF-A in both airway and mesenchymal tissue (Scott et al., 2010). "
"This may explain the intense signal of the mTOR-S6K-rS6 axis seen in the glandular structure, including its cancer counterpart, AC (Figures 3 and 4)  . Since 4E- BP1 expression has been observed in mesenchymal cells of the lung after birth , there is the possibility that the mTOR/4E-BP1 axis predominantly functions in nonneoplastic mesenchymal tissues. "
[Show abstract][Hide abstract] ABSTRACT: The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth and metabolism in response to diverse external stimuli. In the presence of mitogenic stimuli, mTOR transduces signals that activate the translational machinery and promote cell growth. mTOR functions as a central node in a complex net of signaling pathways that are involved both in normal physiological, as well as pathogenic events. mTOR signaling occurs in concert with upstream Akt and tuberous sclerosis complex (TSC) and several downstream effectors. During the past few decades, the mTOR-mediated pathway has been shown to promote tumorigenesis through the coordinated phosphorylation of proteins that directly regulate cell-cycle progression and metabolism, as well as transcription factors that regulate the expression of genes involved in the oncogenic processes. The importance of mTOR signaling in oncology is now widely accepted, and agents that selectively target mTOR have been developed as anti-cancer drugs. In this review, we highlight the past research on mTOR, including clinical and pathological analyses, and describe its molecular mechanisms of signaling, and its roles in the physiology and pathology of human diseases, particularly, lung carcinomas. We also discuss strategies that might lead to more effective clinical treatments of several diseases by targeting mTOR.
International journal of clinical and experimental pathology 06/2011; 4(5):476-95. · 1.89 Impact Factor
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