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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).
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.
Energy Metabolism, Metabolic Sensors, and Nutritional Interventions in Polycystic Kidney Disease
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Sonu Kashyap, Eduardo Nunes Chini
Therefore, FR without malnutrition is a highly effective and reproducible approach that does not involve any genetic manipulations and provides the beneficial effects in aging as well as increased longevity.15,94 Interestingly, beneficial effects of FR are mediated by several metabolic sensors such as the AMPK, mTOR-S6 K, and SIRT1 pathways.15,94,102 FR leads to the inhibition of the mTOR-S6 K pathway and activation of AMPK.8 Furthermore, metabolic sensors regulated by FR also appear to be involved in cystogenesis in PKD. Therefore, pharmacological intervention involving these pathways could mimic some features of FR which might be beneficial in this cystic disease. Our group postulated that FR may provide protection against the development of ADPKD.5 In a study published in the Journal of the American Society of Nephrology (JASN), we clearly demonstrate for the first time that FR can ameliorate cystic disease burden in animal models of ADPKD.5 Our data were independently confirmed and expanded by the group of Dr. Thomas Weimbs.7 These studies opened new avenues for the understanding of ADPKD pathogenesis and treatment. In particular, we postulated that signaling pathways differentially regulated in the kidneys of ad libitum and FR ADPKD animals may provide a clue into the pathophysiology of ADPKD.
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].
From next-generation sequencing to targeted treatment of non-acquired epilepsies
Published in Expert Review of Molecular Diagnostics, 2019
Rikke S. Møller, Trine B. Hammer, Guido Rubboli, Johannes R. Lemke, Katrine M. Johannesen
In the last years, several studies have shown a link between somatic brain mutations causing an upregulation of the mTOR pathway and malformations of cortical development (MCD) such as FCD or hemimegalencephaly (HME) [96–99]. MRI indistinguishable MCDs can be caused by germline loss-of-function mutations in DEPDC5, NPRL2, NPRL3, and TSC1/2, or by somatic mutations in AKT3, MTOR, and PIK3CA. Mutations in the same gene can cause a disease continuum from FCD to HME to bilateral brain overgrowth, which is reflecting the progenitor cell and developmental time when the mutation occurred [72,100–107]. The exact mechanisms by which mutations of the mTOR partway results in MCDs and epilepsy are poorly elucidated. MTOR is involved in the phosphorylation of several substrates, including Protein S6 that controls cell growth. It has been shown that hyperphosphorylation of Protein S6 can augment protein synthesis which can result in cellular enlargement. Furthermore, studies of tissue from FCD type IIb have shown that enlarged balloon cells are not able to initiate epileptic activity, whereas dysmorphic pyramidal neurons and cytomegalic interneurons are hyperexcitable and can be directly involved in originating and spreading of epileptic activity [108]. These results support a direct role of the mTOR pathway in epileptogenesis; however, the molecular mechanisms that translate mTOR upregulation in neuronal hyperexcitability are still unknown. Currently, patients with intractable focal epilepsy due to FCD or HME can only rely on surgical resection for attempted seizure control. However, the link between FCD, HME, and the mTOR pathway may confer hope that mTOR inhibitors can be effective for patients with FCD and HME [100].
Isolation and cultivation of candidate phyla radiation Saccharibacteria (TM7) bacteria in coculture with bacterial hosts
Published in Journal of Oral Microbiology, 2020
Pallavi P. Murugkar, Andrew J. Collins, Tsute Chen, Floyd E. Dewhirst
A concatenated protein tree was generated in Anvi’o [33] using the methods described by Shaiber et al. [34] with minor modifications. The following ribosomal proteins were used: L1, L2, L3, L4, L5, L6, L13, L14, L16, L18p, L19, L21p, L22, L23, L29, S2, S3, S6, S7, S8, S9, S11, S12_S23, S13, S15, S17 and S19. A maximum likelihood phylogenetic tree was computed using IQ-TREE [35] with the WAG general matrix model [36] and 1000 bootstrap replicates. The output treed was edited in MEGA X [31]. Average nucleotide identity (ANI) was computed using Anvi’o ‘anvi-compute-genome-similarity’ that uses blastn+ [37].