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Naturally Occurring Histone Deacetylase (HDAC) Inhibitors in the Treatment of Cancers
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Sujatha Puttalingaiah, Murthy V. Greeshma, Mahadevaswamy G. Kuruburu, Venugopal R. Bovilla, SubbaRao V. Madhunapantula
Class IIb HDACs consisting of HDAC6 and HDAC10 are generally present in the cytoplasm and harbor a long tail domain at the C-terminus (Seto and Yoshida, 2014). HDAC6 contains two deacetylase domains and a C-terminal zinc finger ubiquitin-binding domain, whereas HDAC10 has only one deacetylase domain and a leucine-rich repeat at C-terminus (Zhang et al., 2006). Studies have shown that HDAC6 deacetylates α-tubulin, cortactin, chaperones and IFNαR, thereby regulating autophagy (Ran et al., 2015).
Angiogenesis and Roles of Adhesion Molecules in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
Asmita Hazra, Saptarshi Mandal
Zinc finger CCCH-type containing 12A (ZC3H12A) or monocyte chemotactic protein–induced protein 1 (MCPIP1), also known as regnase 1, is a 599-amino-acid 66 kDa multifunctional intracellular protein. It contains three functional domains: a PIN domain with endoribonucleolytic activity like RNase-L, a CCCH-type zinc finger domain that mediates AU-rich mRNA binding similar to tristetraprolin (TTP), and a ubiquitin binding domain with deubiquitinase activity. It can act as a rapid-response endoribonuclease antimicrobial protein that is expressed in high levels by psoriatic keratinocytes and reduces to normal levels after clinical treatments with anti-IL17A/IL17R neutralizing antibodies. In monocytes, regnase 1 downregulates IL6 and IL12B mRNAs, thus suppressing inflammation, whereas in T cells, it reduces T-cell activation by targeting c-Rel, Ox40, and IL2 mRNAs.
Autophagy regulates X-ray radiation-induced premature senescence through STAT3-Beclin1-p62 pathway in lung adenocarcinoma cells
Published in International Journal of Radiation Biology, 2022
Yu-Ting Tian, Li-Ping Ma, Chun-Yan Ding, Meng-Meng Liu, Si-Nian Wang, Mei Tian, Ling Gao, Qing-Jie Liu
Currently, autophagy can be divided into selective and nonselective autophagy, depending on whether autophagy is selective for degradation. Selective autophagy can selectively remove protein polymers and damaged organelles through receptor proteins while p62 is the first receptor with this function. Selective autophagy usually requires the presence of adaptor proteins such as p62 and NBR1. These proteins have a ubiquitin-binding domain and LC3 interaction motif; therefore, they can bind ubiquitin-modified proteins and transport them to autophagosomes. Increasing evidence supports the notion that p62 dysfunction can lead to the blockage of a variety of signaling pathways and abnormal protein aggregation, which can induce neurodegenerative diseases, immune diseases, human tumors, and other diseases. The accumulation of p62 increases the possibility of tumourigenesis, which may be related to its activation of two reactive oxygen species scavenging systems, Nrf2 and NF-κB; finally, thereby activating the cell proliferation signaling pathway. At the same time, p62 accumulation also makes the genome unstable and promotes tumor development. Therefore, reducing p62 levels by activating autophagy is an effective anti-tumor strategy.
Misconnecting the dots: altered mitochondrial protein-protein interactions and their role in neurodegenerative disorders
Published in Expert Review of Proteomics, 2020
Mara Zilocchi, Mohamed Taha Moutaoufik, Matthew Jessulat, Sadhna Phanse, Khaled A. Aly, Mohan Babu
Considerable insights have also been gained into the involvement of RAB GTPases in mitophagy [111–113]. For instance, mt RAB GTPase-activating proteins (TBC1D15, D17) inhibit the activity of RAB7 upon Parkin activation and mediate the encapsulation of damaged mt by binding FIS1 and LC3/GABARAP [113]. Mt can also be sequestered in RAB5-early endosomes in a Parkin and Beclin1-dependent manner, thus mediating their degradation by lysosomes [112]. Similarly, a guanine nucleotide exchange factor of endosomal RAB protein, RABGEF1, containing ubiquitin-binding domains, is recruited to damaged mt in a Parkin-dependent manner, and directs downstream RAB protein, RAB7A, whose depletion inhibits the assembly of ATG9A (an essential autophagy protein) vesicles near damaged mt. This suggests RABs at damaged mt are crucial regulators of mitophagy through the recruitment of ATG9A vesicles [111].
Structure-based design generated novel hydroxamic acid based preferential HDAC6 lead inhibitor with on-target cytotoxic activity against primary choroid plexus carcinoma
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2019
Shaymaa E. Kassab, Samar Mowafy, Aya M. Alserw, Joustin A. Seliem, Shahenda M. El-Naggar, Nesreen N. Omar, Mohamed M. Awad
HDAC6 is found to be overexpressed in several cancer cell types39–44, it is also implicated in the onset or the progression of many neurodegenerative diseases45–47 and autoimmune disorders48–50. HDAC6 protein is the only isoform with two active deacetylase domains that are identical and function independently51; the linker between the two domains is the dynein motor binding (DMB) domain, and cytoplasmic retention signal (SE14) motif that enables the enzyme to reside in the cytoplasm to perform its functions regularly (Figure 1)52. Zinc finger ubiquitin binding domain (BUZ) is located at the C-terminal and is absent in the other HDAC isoforms14. Due to that unique structure, and cytoplasmic localisation, HDAC6 is able to deacetylate non-histone proteins; such as α-tubulin, heat shock protein 90 (Hsp90), and cortactin53. The post-translational modification of these non-histone proteins contribute to cancer cell proliferation, migration, protein homoeostasis, regulation of expression of critical immune modulators, the stability and activity of transcriptional factors such as hypoxia inducible factors (HIFs), the activity of estrogenic and androgenic receptors, and platelet aggregation in coagulation process14,36,44,53,54.