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Molecular Mechanisms of Brain Insulin Signaling 1
Published in André Kleinridders, Physiological Consequences of Brain Insulin Action, 2023
Simran Chopra, Robert Hauffe, André Kleinridders
Activated MAPKs affect a multitude of downstream processes, such as the translation of mRNA to proteins. This is influenced by MAPK phosphorylation of 40S ribosomal protein S6 kinase (RPS6) to activate ribosomal protein S6 and thereby increase translation (57). MAPKs also regulate the levels and activities of several transcription factors, leading to altered transcription of genes which is consequently important for the cell cycle. Thus, MAPK stimulates cell growth and mitochondrial function in insulin-sensitive cells (58, 59) (Figure 1.1).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Overall, rapamycin and its analogues are generally well tolerated and can induce prolonged disease stability and even tumor regressions in subsets of patients. As part of a Precision Medicine approach (see Chapter 11), activated S6K or its substrate, the ribosomal protein (S6), as well as 4E-BP1 (i.e., phospho-S6K, phospho-S6, and phospho-4E-BP1, respectively), are being evaluated for use as pharmacogenomic biomarkers in tumors because it may be possible to use their presence or absence as a means to select patients who may benefit from mTOR inhibitors. Interestingly, studies have shown that rapamycin and its analogues given late in life to genetically heterogeneous mice can extend their lifespan.
The Rous Sarcoma Virus Oncogene and its Proto-Oncogene Counterpart
Published in Pimentel Enrique, Oncogenes, 2020
The ribosomal protein S6 is also phosphorylated by the action of pp60v-src.118 The phosphorylation occurs not in tyrosine but in serine residues and a similar modification is induced by a variety of tumor viruses as well as by serum or phorbol ester.119,120 Microinjection of pp60v-src into Xenopus oocytes increases phosphorylation of protein S6 and accelerates the rate of progesterone-induced meiotic maturation.121 pp60v-src Also phosphorylates three glycolytic enzymes (enolase, phosphoglycerate mutase, and lactate dehydrogenase) in cultured cells.122 These enzymes catalyze three out of the last four steps of glycolysis and their modification may contribute to the high rate of aerobic glycolysis observed in transformed cells, evident from the rapid glucose uptake and lactate production observed in cells transformed by different agents, including RSV.
Combination of mTOR inhibitor PP242 and AMPK activator metformin exerts enhanced inhibitory effects on colorectal carcinoma cells in vitro by blocking multiple kinase pathways
Published in Journal of Chemotherapy, 2023
Cuicui Sun, Xiaoyan Yang, Zhi Jin, Zuhua Gao
mTOR constitutes a major pathway for cell proliferation, survival, differentiation, and angiogenesis [17, 18]. It is a catalytic subunit composed of at least two distinct multi-protein complexes designated as mTOR complex 1 and 2 (mTORC1 and mTORC2) [19]. mTORC1 comprises mTOR, regulatory-associated protein of mTOR (Raptor), mLST8/GbL, Deptor, and proline-rich AKT substrate 40 [20]. mTORC2 consists of mTOR, rapamycin-insensitive companion of mTOR (Rictor), mLST8/GbL, Protor, Deptor, and mammalian stress-activated protein kinase interacting protein [21]. mTORC1 controls protein synthesis rate through phosphorylation and activation of its substrates, S6K1 and 4E-BP1. Once phosphorylated, S6K1 activates ribosomal protein S6, which stimulates mRNA translation with a 5′ oligopyrimidine tract. The phosphorylation of 4E-BP1 releases eIF4E, allowing its association with eIF4G to form the active eIF4F complex, a key component of the protein synthesis machinery that is particularly important for the translation of 5′ capped mRNA. Thus, mTORC1 activation promotes ribosome biogenesis, protein synthesis, and angiogenesis to support cell growth and proliferation [22]. On the other hand, mTORC2 phosphorylates AKT, serum- and glucocorticoid-regulated kinase (SGK), and protein kinase C (PKC), which regulate cell survival and cell cycle progression [23, 24].
Unravelling the health effects of fasting: a long road from obesity treatment to healthy life span increase and improved cognition
Published in Annals of Medicine, 2020
Françoise Wilhelmi de Toledo, Franziska Grundler, Cesare R. Sirtori, Massimiliano Ruscica
In the fasting mode, cellular and metabolic processes are controlled by a complex network of transcriptional regulators. Major regulators are SIRTs, nuclear factor erythroid 2–related factor 2 (NRF2), FOXO1, nuclear factor ‘kappa-light-chain-enhancer’ of activated β-cells (NFkB), hypoxia inducible factor 1 α (HIF-1α), heat shock factor (HSF-1). The decrease of the protein responsive signalling pathway mTOR and of its downstream effector, the ribosomal protein S6 kinase β-1, leads to global protein synthesis inhibition and recycling of macromolecules by autophagy stimulation [60]. In the brain, in addition to raised neuronal stress resistance through bolstered mitochondrial function there is an improvement in antioxidant defences, DNA repair, and stimulation of BDNF production [61,62]. BDNF regulates hippocampal neurogenesis, dendrite morphology and synapse plasticity, and increases production of new neurons from neural stem cells [63]. The decrease in glucose levels in parallel to the rise in ketones during fasting is associated with a decrement in the glucose responsive Ras-AC-PKA pathway, implicated in life span extension [64].
Combined intervention of 17β-estradiol and treadmill training ameliorates energy metabolism in skeletal muscle of female ovariectomized mice
Published in Climacteric, 2020
X. Li, L. Fan, M. Zhu, H. Jiang, W. Bai, J. Kang
Western blot analysis was performed as described previously18. The proteins were extracted from skeletal muscles of both hind limbs (mixed muscles excluding soleus and gastrocnemius). The expression of target proteins was quantified by western blotting and β-actin was measured as an internal control. In brief, aliquots of 30 μg of protein from each sample were separated by 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to nitrocellulose membrane. The membrane was blocked and subsequently probed with primary antibodies (1:1000) at 4 °C overnight. The membrane was then washed and incubated with a horseradish peroxide-conjugated secondary antibody (1:4000) at room temperature for 1 h. The protein expression level was quantified with ImageJ software. The antibodies to mammalian target of rapamycin (mTOR; CST no. 2983), phosphor-mTOR at Ser2448 (p-mTOR; CST no. 2971), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α; CST no. 2178), ribosomal protein S6 (CST no. 2217), ribosomal protein phosphor-S6 at Ser235/236 (p-S6; CST no. 4858), p70 ribosomal S6 kinase 1 (S6K1; CST no. 2708), and phosphor-S6K1 at Thr389 (p-S6K1; CST no. 9234) were purchased from Cell Signaling Technology (Boston, Massachusetts, USA). The antibody to β-actin (no. TA-09) was purchased from Beijing ZSGB Biotechnology (Beijing, China).