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Mitochondrial Dysfunction in Huntington Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
Md. Hafiz Uddin, Marufa Rumman, Tasnuva Sarowar
In 3-nitropropionic acid (3-NP)-induced rat HD model, increased formation of autophagosomes was observed in striatal cells. Biochemical analyses demonstrated active lysosomal cathepsin B and D, as well as conversion of LC3-I to LC3-II. Interestingly, 3-NP increased the expression of tumor suppressor protein 53 (p53) gene and its downstream signaling proteins, including Bax, p53-upregulated modulator of apoptosis (PUMA), and damage-regulated autophagy modulator (DRAM) (Figure 9.2). Inhibition of p53 by specific inhibitor pifithrin-α (PFT) reverses the activation of downstream molecules and 3-NP-induced striatal damage. Additionally, inhibition of autophagy using 3-methyladenine (3-MA) and bafilomycin A1 (BFA) reduces DNA fragmentation and striatal cell death (Zhang et al. 2009). In fact, postmortem analysis of brains of HD patients showed an increase in endosomal and/or lysosomal organelle, and their multivesicular bodies, which indicate enhanced macroautophagy or mitophagy in neurons (Hirano 2008). These observations recommend that autophagy, at least in part, contributes to mitochondrial dysfunction leading to neurodegeneration through p53 signaling (Zhang et al. 2009).
TP53 in cancer origin and treatment
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
Elena A. Komarova, Peter M. Chumakov, Andrei V. Gudkov
TP53-dependent apoptosis was found to be a major factor contributing to tissue sensitivity to genotoxic stress and TP53 was defined as a major determinant of radiosensitivity and chemosensitivity of tissues responsible for severe side effects of anti-cancer treatment. As indicated above, the propensity of certain tissues to drug-induced apoptosis may limit the effectiveness of many current therapies. Studies using mouse models have clearly documented the importance of TP53 for apoptosis in thymocytes, bone marrow and intestinal stem cells (see above); consequently, agents which suppress TP53 function may be effective radio- or chemoprotective agents and/or allow dose intensification of current regimens. Chemotherapy-induced hair loss, another well-known side effect of cancer treatment, was also found to be TP53 dependent (Botchkarev et al., 2000). Temporary suppression of TP53 by chemical inhibitors was, therefore, suggested as a therapeutic approach to reduce damage caused by radiation and chemotherapy to normal tissues (Komarov et al., 1999; Komarova and Gudkov, 1998). Since most advanced solid tumors have lost TP53 function, these inhibitors should not interfere with cell death of most tumor cells. Recently, a small molecule (designated pifithrin-alpha) has been identified that inhibits TP53-mediated transcriptional responses and TP53-induced apoptosis in cultured cells (Komarov et al., 1999). In mice, pifithrin-alpha is a potent radioprotective agent, allowing mice to survive otherwise lethal doses of ionizing radiation.
Intracellular displacement of p53 using transactivation domain (p53 TAD) specific nanobodies
Published in mAbs, 2018
Anneleen Steels, Adriaan Verhelle, Olivier Zwaenepoel, Jan Gettemans
Insight into the relevance of nuclear or cytoplasmic functions of p53 in tumor suppression can also be obtained by equipping the Nbs with a nuclear localization signal (NLS)-tag or a nuclear export signal (NES)-tag. In this way, free diffusion of the protein can be limited to either the nucleus or the cytoplasm.18,63 This is a gentler and more specific way of manipulating the p53 pathway, since it has been shown that small compounds like pifithrin-α also affect other pathways.64 Alternatively, Nbs are valuable tools for spatiotemporal antigen tracking of intracellular proteins.65–67 One could use p53 TAD Nbs to track the cellular movements of both wild type p53 and p53 mutants in response to several cellular stresses, which might help to define how the nuclear and cytoplasmic routes of p53 are coordinated.
p53 inhibition attenuates cisplatin-induced acute kidney injury through microRNA-142-5p regulating SIRT7/NF-κB
Published in Renal Failure, 2022
Guoxiao Chen, Huanzhou Xue, Xiangsheng Zhang, Degang Ding, Shilong Zhang
Pifithrin-α is a pharmacological inhibitor of p53. The effects of pifithrin-α in mice were initially examined to determine the role of p53 in cisplatin-induced AKI in vivo. As shown in Figures 2(A–D), cisplatin treatment induced obvious kidney tubular injury for 48 h, and pifithrin-α treatment partially inhibited renal histological damage, as demonstrated by HE and PAS staining. Importantly, pifithrin‐α treatment also improved renal function, and the BUN and serum creatinine in pifithrin‐α-treated animals decreased compared with those in the cisplatin-treated group (Figures 2(E,F)).