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Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
It is known since a variety of years that PD (both the sporadic and familiar form) is related to oxidative stress and mitochondrial dysfunction associated with impaired ATP synthesis (Schapira, 2008). To the mitochondrial proteins belong Pink1 (PTEN-induced kinase 1, serine/threonine-protein kinase) and parkin (E3 ubiquitin ligase), the gene products of Pinkl and parkin. Parkin ubiquitinates impaired mitochondrial proteins (among others due to ROS-induced misfolding) for organelle degradation. Pink1 is important for mitochondrial quality control as it identifies impaired mitochondria for degradation. In the case of damaged mitochondria, due to a decreased membrane potential (depolarized mitochondria) the protein accumulates at the outer membrane where it recruits parkin. Parkin is activated by PINK1-dependent phosphorylation of ubiquitin; for this dimeric Pink1 itself is activated in a complex with other membrane components by intermolecular autophosphorylation. Hence, Pink1-phosphorylated ubiquitin chain on mitochondria is the putative receptor for Parkin (Matsuda, 2016). This process leads to predominantly autophagic degradation. Mutations of either Pink1 or Parkin cause Parkinson’s disease in humans.
Treatment of Carbon Monoxide Poisoning
Published in David G. Penney, Carbon Monoxide, 2019
Of these theories regarding insulin’s neuroprotective activity, however, the most recent highlights its role in stimulating second messengers, and emphasizes its potential genomic effects — that is, the regulation of protein synthesis, enzymatic activity, and the signaling of cell proliferation. It is well established that the neonatal brain is rich in insulin-like growth factor receptors. Indeed, insulin is similar in structure to other growth factors such as PDGF, EGF, and IGF-1. Such peptides are involved in basic neuron development and differentiation. Once bound to its receptor, like other growth factors, insulin triggers signal transduction by internal autophosphorylation of tyrosine on the insulin receptor, which subsequendy enhances further phosphorylation reactions of other tyrosine-containing substrates by tyrosine kinase, also located on the insulin receptor (Figure 3).
DNA Damage Response Research, Inherent and Future Nano-Based Interfaces for Personalized Medicine
Published in Yubing Xie, The Nanobiotechnology Handbook, 2012
Madhu Dyavaiah, Lauren Endres, Yiching Hsieh, William Towns, Thomas J. Begley
ATM is recruited by the MRN complex to double-strand breaks, where inactive dimeric ATM dissociates and becomes active monomeric ATM by autophosphorylation at serine 1981. Autophosphorylation of ATM also activates its kinase activity for use in downstream signaling (Cortes et al. 2003). Some controversial data in mouse models indicated that auto-phosphorylation at serine 1981 is dispensable for ATM activation (Daniel et al. 2008, Pellegrini et al. 2006). However, recent data have demonstrated that autophosphorylation at serine 1981 is required for ATM monomerization and retention on DNA lesions through association with mediator of DNA damage check point protein 1 (MDC1; So et al. 2009). Following the recognition of DNA damage by sensor proteins, ATM and ATR kinases immediately activate and phosphorylate mediators that function as recruiters for additional ATM/ATR substrates or as scaffolds to mediate DNA damage response (DDR) complex formation.
Deciphering the resistance mechanism of RET kinase mutant against vandetanib and nintedanib using molecular dynamics simulations
Published in Journal of Experimental Nanoscience, 2021
Guodong Zheng, Shenqian Xu, Wuxia Liu, Tingting Du, Jingfeng Zhang, Minyu Li, Chen Cai, Hong Shi
The RET protein, encoded by the gene RET (abbreviation for the ‘REarranged during Transfection’), is a transmembrane receptor belonging to the receptor tyrosine kinases (RTKs) family [1, 2]. As an important promoter for the development of human kidneys and enteric nervous system [3–5], RET receives the extracellular signals such as the glial cell line-derived neurotropic factor (GDNF) with co-receptors [6], activates its kinase activity through homodimerization and autophosphorylation [7], and ultimately facilitates the down-stream signalling cascades including MAPK, PI3K, and PKA pathways to activate cell proliferation [8–11]. Aberrant activation of RET resulting from either oncogenic mutations of RET gene or chromosomal rearrangements can lead to the occurrence of solid tumours such as medullar thyroid cancer (MTC) and non-small cell lung cancer (NSCLC) [12–14].
Impact of stainless-steel welding fumes on proteins and non-coding RNAs regulating DNA damage response in the respiratory tract of Sprague-Dawley rats
Published in Journal of Toxicology and Environmental Health, Part A, 2018
Jayaraman Krishnaraj, Abdul Basit Baba, Periasamy Viswanathan, Veeran Veeravarmal, Viswalingam Balasubramanian, Siddavaram Nagini
ATM, a key player that orchestrates DDR, undergoes autophosphorylation at Ser1981 in response to DSBs, triggering phosphorylation of over 700 target proteins including those involved in DDR, such as p53, a master regulator of genomic stability (Laptenko and Prives 2017; Shiloh and Ziv 2013). Phosphorylation of Nbs1 by ATM promotes HR, a critical determinant of DSB repair pathway choice (Kowalczykowski 2015). ATM directly phosphorylates the MRN-interacting protein CtIP, a key nuclease required for resection initiation (Wang et al. 2013), prompting the removal of Ku from single-ended DSB ends to enable HR to proceed over NHEJ (Britton, Coates, and Jackson 2013). ATM also activates NHEJ by phosphorylating 53BP1 at Ser25 (Harding, Coackley, and Bristow 2011). In addition, ATM phosphorylates BRCA1 that promotes error-free HR at the expense of 53BP1-mediated error-prone NHEJ (Hustedt and Durocher 2016). It is possible that phosphorylation of ATM by welding fumes triggers a cascade of phosphorylation and activation of multiple proteins involved in HR and NHEJ. While phosphorylation of BRCA1, Mre11 and Nbs1 with upregulation of Rad50 confirms activation of HR, overexpression of 53BP1, DNA-PKcs, Ku80 and XLF indicates NHEJ activation. Most importantly, phosphorylation of the histone variant, H2AX at Ser139 by ATM essential for recruiting DDR factors to damaged chromatin formation of MRN, BRCA1, and 53BP1 foci may play acritical role in welding fume-induced DDR.
A convergent fabrication of programmed pH/reduction-responsive nanoparticles for efficient dual anticancer drugs delivery for ovarian cancer treatment
Published in Journal of Experimental Nanoscience, 2023
Haiyan Zhang, Youlin Yang, Yi Chen, Xiahui Zhang, Xiaopei Chen
An anticancer drug called Gefitinib (GFT) is the first specific inhibitor of the tyrosine kinase region of the epidermal growth factor receptor (EGFR) tyrosine-kinase domain [25]. The transmembrane glycoprotein epidermal growth factor has unique tyrosine kinase receptors that govern high cellular proliferation and expression levels in cancer [26]. Solid tumors, including ovarian, lung, colorectal, and brain, will likely exhibit more elevated EGFR. To suppress cancer cell proliferation, GFT inhibits the kinase activity of wild-type and specific activating mutations of the EGF receptor, thereby blocking tyrosine residues linked with the receptor’s autophosphorylation, preventing further downstream signaling [27–29].