Developmental Diseases of the Nervous System
Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw in Hankey's Clinical Neurology, 2020
HI is believed to be due to a somatic cell mosaicism involving pigmentary genes. However, a variety of mosaic chromosomal abnormalities have also been reported including trisomy 18, triploidy, and tetrasomy 12p, and mutations in the X chromosome. It is hypothesized that the chromosomal anomalies disrupt expression or function of pigmentary genes. Pigmentary genes control a variety of processes, including melanoblast migration from the neural crest in fetal life. It is suggested that the pigmentary pattern that follows Blaschko's lines is the result of the migration of two different clones of cells during embryogenesis. The complex malformation of HI is postulated to be due to somatic genetic changes early in development, whereas patients with isolated skin manifestations are felt to be due to somatic changes in the skin alone, later in development. Mutations in the PI3K-AkT3-mTOR pathway have been seen in some patients.
Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
The serine/threonine kinase Akt, named after a strain of mice and also known as Protein Kinase B (PKB), has a critical role in the PI3K-Akt signaling pathway (Figure 6.87) which is involved in a number of cellular processes including proliferation, survival, glucose metabolism, genome stability, transcription, protein synthesis, and neovascularization. Inhibition of Akt results in a reduction in cell-cycle progression and tumor growth. Akt has three isoforms, Akt1 (PKBα), Akt2 (PKBβ), and Akt3 (PKBγ), all of which share high sequence homology and are composed of similar structural domains. The catalytic structural domain has highly homology with Protein Kinases A (PKA) and C (PKC), and other cAMP-dependent protein kinases.
Micronutrients in Prevention and Improvement of the Standard Therapy in Hearing Disorders
Kedar N. Prasad in Micronutrients in Health and Disease, 2019
Although increased oxidative stress is involved in the pathogenesis of hearing disorders, only a few studies are available on the effects of this biochemical event on changes in the expression of miRs in the cochlear hair cells. Increased oxidative stress induced by t-BHP (tert-butylhydroperoxide) enhanced the expression of 24 microRNAs. Among these, 6 microRNAs: miR-1934, miR-411, miR-717, miR-503, miR-467e, and miR-699o that regulate apoptosis and proliferation of the cochlear hair cells were strongly expressed.125 ROS generated by the treatment with t-BHO increased the expression of 35 microRNAs and decreased the expression of 40 microRNAs, and inhibited the proliferation of hair cells (HE1-C1).126Reactive oxygen species (ROS) generated by exposure to ionizing radiation enhanced the expression of miR-207 in the hair cell line (HE1-OC1). This microRNA increased radiation-induced apoptosis and DNA damage by inhibiting its target protein AKt3. This was further supported by the fact that inhibiting the levels of AKt3 mimicked the effects of miR-207.127In diabetic mice with a high level of internal oxidative stress, the expression of miR-34a was elevated and the level of SIRT1 was inhibited and promoted apoptosis in the hair cells (HE1-OC1). This finding indicated that downregulation of miR-34a may help in diabetic-related hearing loss.128
LINC02163 promotes colorectal cancer progression via miR-511-3p/AKT3 axis
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2020
Junwen Ma, Lihai Zhang, Anquan Shang, Hu Song, Jiege Huo, Mingjian Zhang, Liuqin Jiang
AKT3 is a member of the AKT family, which takes key roles in a variety of cell growth processes, such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration [25]. AKT3 has been demonstrated as oncogenes in CRC through PI3K/AKT signalling pathway [26]. In our study, we found that AKT3 was upregulated in CRC patients and positively correlated with the abundance of LINC02163 in CRC tissues, indicating the pro-tumoral role of AKT3 in CRC (Figure 5(A,B)). Additionally, both mRNA and protein level of AKT3 in CRC cells transduced with sh-LINC02163 were greatly rescued by miR-511-3p inhibitor transfection (Figure 5(C,D)). Cell proliferation assays displayed CRC cells growth was elevated by inhibition of miR-511-3p or overexpression of AKT3 (Figure 5(E,F)). As for mechanism investigation, knockdown of LINC02163 led to cell cycle arrest in G0/G1 stage while transfection of miR-511-3p or AKT3 abolished cycle arrest in LINC02163-depletion CRC cells, indicating LINC02163 promoted cell proliferation through modifying cell cycle progress (Figure 5(G)).
Overexpression of miR-181a regulates the Warburg effect in triple-negative breast cancer
Published in Climacteric, 2023
Y. Wang, H. Tahiri, C. Yang, M. Gu, X. Ruan, P. Hardy
To gain insight into the mechanisms underlying miR-181a-mediated suppression of the Warburg effect, we focused on several direct targets that have been implicated in the regulation of glycolysis in cancer cells. For example, AKT3 was identified as a direct target of miR-181a based on the presence of relevant binding sites within its 3′ untranslated region [38]. AKT3 is a member of the protein kinase B (PKB/AKT) family, which is a group of intracellular kinases that modulate cell proliferation and survival [39]. AKT3 has been identified as a critical mediator of the Warburg effect. Furthermore, both HIF-1 and PGRMC1 contribute to glucose uptake and metabolism and promote cancer cell survival and metastasis [40,41]. Thus, we performed quantitative PCR and western blot analysis to determine whether miR-181a regulates the expression of any or all of these genes upon its expression in MDA-MB-231 cells. As anticipated, overexpression of miR-181a resulted in significant reductions in the levels of AKT3, HIF-1α and PGRMC1 mRNA and protein (Figure 3). Taken together, these results suggest that miR-181a may modulate the expression of key factors associated with the AKT3/HIF-1α signaling pathway in TNBC cells, thereby suppressing the Warburg effect.
Transcriptome profiling of cervical cancer cells acquired resistance to cisplatin by deep sequencing
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Yamin Wang, Linna Liu, Zhong Chen
Therefore, the connection between AKT3 and cisplatin resistance in cervical cells is further studied in this work. We first reported that AKT3 takes a crucial part in cisplatin resistance in cervical cells. It has been observed that AKT3 is highly expressed in cisplatin resistance Hela/DDP cells than cisplatin sensitive Hela cells both in mRNA and protein level. qPCR analysis also showed that mRNA measured matched their sequencing results. In addition, knockdown of AKT3 increased sensitivity to cisplatin and apoptosis. After treating with MK-2206 2HCl, Hela/DDP cells showed more sensitive to cisplatin as well. Western blot analysis further indicated that MK-2206 2HCl significantly decreased expression of p-AKT. Results suggested that AKT3 takes an important part in many aspects of cancer biology which involves proliferation, survival, apoptosis and drug resistance of cancer cells.
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