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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
Moreover, insulin-induced AKT activation is crucial to modulate gene regulation via blocking the activity of FOXO transcription factors. There are four members of the FOXO family which include FOXO1, FOXO3, FOXO4, and FOXO6, where FOXO1 and FOXO3 are expressed in almost all tissues. AKT phosphorylates FOXO proteins at several serine residues (50) which facilitates the binding of FOXOs to proteins of the 14-3-3 family. This interaction leads to the nuclear exclusion of FOXO proteins and inhibition of their transcriptional activity (50). It has been suggested that the FOXO1 function is an important regulator of food intake and energy balance (51). While insulin inhibits FOXO1 activity and reduces food intake, active FOXO1 enhances food intake. FOXO6 is primarily expressed in the hippocampus of the brain and liver. It has been observed that upon whole-body deletion of FOXO6, although the mice exhibited normal learning behavior, they displayed impaired memory consolidation. In addition, through the process of stereotactic injection of viruses into the hippocampus of wild-type adult mice, it was revealed that FOXO6 activity in the hippocampus was important to promote memory consolidation (52, 53), indicating that insulin action can affect memory via FOXO6 regulation.
Hibernation and Aging
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Cheng-Wei Wu, Kenneth B. Storey
Another class of transcription factor that is prominently involved in the insulin signaling pathway and longevity are the forkhead box O (FOXO) proteins, which in mammals is comprised of a family of four members, FOXO1, 3, 4, and 6. The FOXO transcription factors are directly phosphorylated and negatively regulated by insulin signaling cascade through the Akt kinase, and similar to Nrf-2, the FOXO proteins can be activated in the presence of stress to induce downstream genes involved in cellular protective responses that include cell cycle arrest, DNA repair, redox balance, apoptosis, and many more (Figure 34.3a) (Eijkelenboom and Burgering 2013, Morris et al. 2015). In genome-wide association studies in human set out to identify “long-lived” genes, it was shown that genetic variations and single-nucleotide polymorphisms within the foxo3a gene was significantly associated with the longevity of centenarians (Willcox et al. 2008, Flachsbart et al. 2009). Activation and overexpression of FOXO protein in the fat body of Drosophila can increase life span by 15.5% in males and 19.4% in females (Hwangbo et al. 2004). Conversely in C. elegans, a deletion to the FOXO ortholog DAF-16 significantly reduces the worm's life span compared to the wild type, and loss of DAF-16 largely suppress the long-lived phenotype of the DAF-2 insulin receptor mutant (Lin et al. 2001). And in mice, protein levels of FOXO3 and FOXO4 have been shown to decline by 25% and 18% respectively with age (Furuyama et al. 2002). These findings suggest that like Nrf-2, an increase in activity and expression of the FOXO proteins may have beneficial effects on life span. In ground squirrels, the total levels FOXO3a protein is overexpressed is by 3.6-fold in the skeletal muscle during hibernation, and this is accompanied by an increase in its nuclear localization and transcriptional activation of its downstream genes that include cell cycle inhibitors p27 and cyclin G2, and the antioxidant enzyme catalase (Figure 34.3b–d) (Wu and Storey 2014).
Roles of mTOR signaling in spermatogenesis
Published in C. Yan Cheng, Spermatogenesis, 2018
Compared to mTORC1, mTORC2 complex is less sensitive to rapamycin. However, prolonged rapamycin inhibits mTORC2 signaling in vitro and in vivo.23,24 mTORC2 directly activates AKT at its hydrophobic motif (Ser473) and with phosphorylation at other sites further phosphorylates substrates including forkhead box O1/3a (Foxo1/3a), TSC1/2, and glycogen synthase kinase alpha/beta (GSK3α/β). Through a germline stem cell culture system, Lee and colleagues have reported that activation of AKT kinase is observed in GDNF-treated SSCs.67 Consistent with our recent study, phosphorylated AKT is one of the dramatically increased phosphorylated proteins upon GDNF stimuli identified by quantitative mass-spectrometry-based proteomic and phosphoproteomic analyses.69 Constitutive activation of AKT by transfecting with myr-Akt-Mer plasmid substantially promotes proliferation of SSCs even in the absence of GDNF (Figure 16.1).67 Goertz and colleagues generated germline conditional Foxo1 knockout and Foxo1/3/4 triple knockout mice to investigate the function of Foxos in the mouse testes, particularly in SSCs self-renewal and differentiation.68 Conditional Foxo1-deficient mice are sterile, with distinct defects in SSCs maintenance and initiation of spermatogenesis (Figure 16.1). Although Foxo3 and Foxo4 are dispensable for germ cell development, Foxo1/3/4 triple knockout mice exhibit more severe spermatogenic defects, indicating the members of Foxo family compensate their functions. These findings indicate the transcriptional factor FOXO1, one downstream target of AKT and AKT kinase itself are required for maintaining SSCs. Goertz and colleagues further conditionally inactivated Pten or 3-phosphoinositide-dependent protein kinase 1 (Pdk1) to determine whether Foxos regulate SSCs function through PI3K-AKT signaling. Indeed, Pten mutant gradually depletes germ cells in an age-dependent manner, which indicates Pten shares similar roles in maintaining SSCs function with FOXOs (Figure 16.1).68Pdk1 loss attenuates AKT phosphorylation and subsequently constitutive Foxo1 activation, and no obvious defects in SSCs self-renewal and differentiation were observed in Pdk1 mutant testes (Figure 16.1).68 These results strongly suggest Foxo1 acts through PI3K-AKT to regulate SSCs self-renewal and PI3K-AKT signaling is crucial for SSCs maintenance. Moreover, Rictor has a germline-specific role in maintaining normal spermatogonial differentiation, suggesting mTORC1 and mTORC2 functions may overlap during spermatogonial differentiation.71
Identification of novel mycocompounds as inhibitors of PI3K/AKT/mTOR pathway against RCC
Published in Journal of Receptors and Signal Transduction, 2022
Ravi Prakash Yadav, Srilagna Chatterjee, Arindam Chatterjee, Dilip Kumar Pal, Sudakshina Ghosh, Krishnendu Acharya, Madhusudan Das
Gene expression studies quantify the expression of gene products derived from their coding gene counterparts, as well as provide crucial information regarding drug-induced gene regulation. In silico gene expression studies revealed that astrakurkurone downregulates the activity of DONSON [33] and SOX4 [34] genes. These genes are involved in cancer cell proliferation, invasion migration and drug resistance in RCC and are found to be downregulated by astrakurkurone. Astrakurkurone also upregulates the activity of TRIM13, IL4 and FOXO4 Increased TRIM13 expression reduced NF-kB, MMP-9, and p-AKT levels as well as the capacity of 786-O cells to migrate and invade [35]. IL4 has shown antitumor effects in malignant mice models and also inhibited the tumor cell growth in in-vitro experiments [36]. FOXO4 induces apoptosis by upregulating Bim in the mitochondria-dependent pathway [37]. Ergosta-4,6, 8-(14) 22-tetraene-3-one downregulates the activity of DONSON [33], ADORA2B [38] and CDCA4 [39] (Table 4). These genes have been involved in providing a conducive environment to renal cancer cells which leads to proliferation and metastasis of cancer cells and ergosta-4,6, 8-(14) 22-tetraene-3-one regulated these genes by downregulating their activity.
Targeting Autophagy In Disease: Recent Advances In Drug Discovery
Published in Expert Opinion on Drug Discovery, 2020
Dasol Kim, Hui-Yun Hwang, Ho Jeong Kwon
FoxO transcription factor family members (FoxO1, FoxO3, FoxO4, and FoxO6) have established roles in diverse cellular functions such as aging, longevity, and development [30]. Similar to the MiT/TFE family, the FoxO transcription factor family is mostly controlled by phosphorylation [31]. AKT/JNK kinase signaling is a major upstream regulator for FoxO1, FoxO3, and FoxO4, but less for FoxO6 due to its lack of a C-terminal AKT-dependent site [30,32]. Among these, FoxO3 [33] and FoxO1 [34] were reported to be autophagy gene transcription factors. A recent study exhibited the relevance of FoxO4 to autophagy gene expression through a triple genetic deletion of FoxO1, FoxO3, and FoxO4 in muscle [35]. However, it is currently unclear whether FoxO4 binds directly to the promoter region of autophagy genes. The FoxO family is regarded as another pivotal modulator for cellular homeostasis through autophagy, as these members have central roles in diverse diseases.
The protective effect of beta-casomorphin-7 via promoting Foxo1 activity and nuclear translocation in human lens epithelial cells
Published in Cutaneous and Ocular Toxicology, 2018
Lihua Zhu, Jia Li, Dayang Wu, Bing Li
The Foxo family of transcription factors includes Foxo1, Foxo3a, Foxo4, and Foxo6 in mammal9. Foxos are ubiquitously expressed10. Foxo proteins play a crucial role as transcriptional activators and are involved in a wide range of cellular processes that regulate metabolism, apoptosis, and cellular oxidative stress responses11–13. Foxo1 was one of the earliest known members of the Foxo family. Also, Foxo1 plays as a crucial protective role in multiple cellular processes, such as antioxidative responses, when activated and transferred to the nucleus. Increased Foxo1 activities and mutual combination with other proteins that are associated with cellular activity, such as the cell cycle, DNA repair, oxidative stress, and apoptosis, enhance the transcription activity of Foxo1, against oxidative stress14–16. The cell’s oxidative state induces nuclear localization of Foxo members. The ability of Foxo1 to resist oxidative damage by nuclear translation has been confirmed. However, hyperglycaemic-induced oxidative stress in HLECs has not been proven.