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SGT-53: A Novel Nanomedicine Capable of Augmenting Cancer Immunotherapy
Published in Raj Bawa, János Szebeni, Thomas J. Webster, Gerald F. Audette, Immune Aspects of Biopharmaceuticals and Nanomedicines, 2019
Joe B. Harford, Sang-Soo Kim, Kathleen F. Pirollo, Antonina Rait, Esther H. Chang
Indirect restoration of p53 functions has also been attempted by aiming at other components of the p53 network [54–56, 89]. It has long been appreciated that alterations in proteins other than p53 can influence p53 functions. Perhaps the most extensively studied are MDM2 and MDMX, two related negative regulators of p53 activity that have ubiquitin ligase activity [90–92]. In response to DNA damage, phosphorylation events inhibit the interaction of p53 with MDM2/MDMX resulting in p53 stabilization with consequent activation of downstream transcriptional targets [93, 94]. Because MDM2/MDMX are negative regulators of p53, overexpression of MDM2/MDMX results in loss of p53 function that can result in oncogenesis [95–97]. In those instances wherein p53 function is lost in a tumor through overexpression of its negative regulators, interventions that down-modulate these regulators or interfere with their interaction with p53 would be expected to restore p53 function for tumor suppression. Such molecules are under study as cancer therapeutics [96, 98–100], but their usefulness may be limited to that subset of cancers wherein wild-type p53 is inhibited by MDM2/MDMX overexpression.
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
p53 is another effector protein that has multiple roles in response to DNA damage. It activates the transcription of genes that participate in DNA repair, cell-cycle regulation, senescence, or apoptosis, depending on the type or the sources of DNA damage. Mdm2 is a negative regulator of p53 by ubiquitin-mediated proteasome degradation. Upon DNA damage, ATM, ATR, and DNA-PK can phosphorylate p53 at serine 15, while CHK1 and CHK2 can phosphorylate p53 at serine 20. Once activated, p53 can transcriptionally regulate the expression of the cyclin-dependent kinase (CDK) inhibitor p21, as well as of the proapoptotic BCL2-associated X protein (BAX) and p53 upregulated modulator of apoptosis (PUMA) proteins that induce cell-cycle arrest, senescence, or apoptosis. Moreover, p53 promotes DNA repair and deoxyribonucleoside triphosphate (dNTP) synthesis (Chen et al. 2005, Shieh et al. 1997, 2000). The preponderance of cancer-associated mutations that disrupt p53’s ability to bind DNA and activate gene transcription underscore the importance of this p53 function in mediating tumor suppression. DNA damage also induces modifications of Mdm2 leading to Mdm2 destabilization and degradation, which effectively reduce its negative regulatory effect on p53 (Wade et al. 2010). This, in combination with p53 N-terminal phosphorylation events and p53 binding to other cellular cofactors, leads to p53 stabilization and transcriptional activation.
Analysis of Molecular Prognostic Factors in Breast Cancer by Artificial Neural Networks
Published in Raouf N.G. Naguib, Gajanan V. Sherbet, Artificial Neural Networks in Cancer Diagnosis, Prognosis, and Patient Management, 2001
B. Angus, T.W.J. Lennard, R.N.G. Naguib, G.V. Sherbet
Mutation of the p53 gene is a frequent event in many types of human cancer including breast carcinoma. Mutation impairs the ability of the cell to degrade the protein which thus accumulates and can be detected by immunohistochemistry. In a small proportion of cases, however, overexpression of p53 can occur in the absence of gene mutation [38]. Whilst the literature is not unanimous [39], most studies have shown that overexpression of p53 detected by immunohistochemistry is associated with markers of tumour aggressiveness, such as high grade and negative hormone receptor status, and also with poor outcome [40–47]. In view of the near universal involvement of p53 in human neoplasia, the potential prognostic significance of related proteins such as MDM2, which bind p53 and promote ubiquitin mediated degradation of the molecule, has been investigated. MDM2 is infrequently mutated but often overexpressed in breast cancer and in one study overexpression was shown to be associated with lymph node metastasis and poor outcome [48].
Effects of tobacco compound 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) on the expression of epigenetically regulated genes in lung carcinogenesis
Published in Journal of Toxicology and Environmental Health, Part A, 2021
Sun Woo Jin, Jong Seung Im, Jae Hyeon Park, Hyung Gyun Kim, Gi Ho Lee, Se Jong Kim, Seung Jun Kwack, Kyu-Bong Kim, Kyu Hyuck Chung, Byung Mu Lee, Sam Kacew, Hye Gwang Jeong, Hyung Sik Kim
MDM2 is an E3 ubiquitin ligase that encodes a negative regulator of the p53 tumor suppressor (Oliner et al. 1992). MDM2 binds to the transcriptional activation domain of p53 to regulate stabilization and activation of p53 (Haupt et al. 1997; Weber et al. 1999). MDM2 overexpression, in particular, was implicated in several tumors, including sarcoma, colon cancer, and gastric cancer (Embade et al. 2012; Oliner, Saiki, and Caenepeel 2016). Previous investigators demonstrated that MDM2 is an optimal therapeutic target in tumors carrying wild-type tumor protein 53 (Burgess et al. 2016; Imanishi et al. 2019; Pellegrino et al. 2015). MDM2 overexpression in fibroblasts enhanced cancer cell invasion and growth of inoculated tumors in mice. Epigenetic modifications, including aberrant DNA methylation, are critical events in carcinogenesis occurrence (Baylin and Ohm 2006). MDM2 might regulate the target proteins interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα), which play an important role in regulating the mitogen-activated protein kinase (MAPK) and NF-κB pathways.