Deciphering the PTM codes of the tumor suppressor p53

Park

et al. 2022

Front. Cell Dev. Biol.

The key tumor suppressor protein p53, additionally known as p53, represents an attractive target for the development and management of anti-cancer therapies. p53 has been implicated as a tumor suppressor protein that has multiple aspects of biological function comprising energy metabolism, cell cycle arrest, apoptosis, growth and differentiation, senescence, oxidative stress, angiogenesis, and cancer biology. Autophagy, a cellular self-defense system, is an evolutionarily conserved catabolic process involved in various physiological processes that maintain cellular homeostasis. Numerous studies have found that p53 modulates autophagy, although the relationship between p53 and autophagy is relatively complex and not well understood. Recently, several experimental studies have been reported that p53 can act both an inhibitor and an activator of autophagy which depend on its cellular localization as well as its mode of action. Emerging evidences have been suggested that the dual role of p53 which suppresses and stimulates autophagy in various cencer cells. It has been found that p53 suppression and activation are important to modulate autophagy for tumor promotion and cancer treatment. On the other hand, activation of autophagy by p53 has been recommended as a protective function of p53. Therefore, elucidation of the new functions of p53 and autophagy could contribute to the development of novel therapeutic approaches in cancer biology. However, the underlying molecular mechanisms of p53 and autophagy shows reciprocal functional interaction that is a major importance for cancer treatment and manegement. Additionally, several synthetic drugs and phytochemicals have been targeted to modulate p53 signaling via regulation of autophagy pathway in cancer cells. This review emphasizes the current perspectives and the role of p53 as the main regulator of autophagy-mediated novel therapeutic approaches against cancer treatment and managements.

Section: P53 Signaling Targets As a Cancer Therapy Via Modulation Of Autophagymentioning

confidence: 99%

p53 Modulation of Autophagy Signaling in Cancer Therapies: Perspectives Mechanism and Therapeutic Targets

Park

et al. 2022

Front. Cell Dev. Biol.

“…There are crystal structures available for the p53 DNA-binding domain, both the WT, alone or bound to different DNA target sites, some hotspot p53 mutations [ 10 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 ], and the p53 TET domain [ 13 ]. However, there is still a lack of data to fully reveal the structural details of the crosstalk between the different domains, including the intrinsically disordered and heavily post-translationally modified N-ter and C-ter domains [ 10 , 16 , 19 , 24 , 81 , 82 ]. This lack of knowledge represents a severe limitation, as p53 is a highly versatile transcription factor that interacts through a wide range of affinity with many DNA RE-binding sites that can be structurally diverse in their internal organization [ 12 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…The transactivation domains are critical for p53 function [ 6 , 17 ] and are located in the amino-terminal sequence (within the first 60 amino acids), a region that is considered to be intrinsically disordered [ 18 , 19 , 20 , 21 ]. Together with the last 30 amino acids in the C-ter, it is subject to several post-translational modifications that impart changes in protein–protein interactions, conformation, subcellular localization, and function to the protein [ 22 , 23 , 24 ]. p53 post-translational modifications were also shown to affect long-range intramolecular interactions between either the N-ter or the C-ter and the DBDs, influencing DNA binding [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Structural Basis of Mutation-Dependent p53 Tetramerization Deficiency

Rigoli

Spagnolli

Lorengo

et al. 2022

IJMS

The formation of a tetrameric assembly is essential for the ability of the tumor suppressor protein p53 to act as a transcription factor. Such a quaternary conformation is driven by a specific tetramerization domain, separated from the central DNA-binding domain by a flexible linker. Despite the distance, functional crosstalk between the two domains has been reported. This phenomenon can explain the pathogenicity of some inherited or somatically acquired mutations in the tetramerization domain, including the widespread R337H missense mutation present in the population in south Brazil. In this work, we combined computational predictions through extended all-atom molecular dynamics simulations with functional assays in a genetically defined yeast-based model system to reveal structural features of p53 tetramerization domains and their transactivation capacity and specificity. In addition to the germline and cancer-associated R337H and R337C, other rationally designed missense mutations targeting a significant salt-bridge interaction that stabilizes the p53 tetramerization domain were studied (i.e., R337D, D352R, and the double-mutation R337D plus D352R). The simulations revealed a destabilizing effect of the pathogenic mutations within the p53 tetramerization domain and highlighted the importance of electrostatic interactions between residues 337 and 352. The transactivation assay, performed in yeast by tuning the expression of wild-type and mutant p53 proteins, revealed that p53 tetramerization mutations could decrease the transactivation potential and alter transactivation specificity, in particular by better tolerating negative features in weak DNA-binding sites. These results establish the effect of naturally occurring variations at positions 337 and 352 on p53’s conformational stability and function.

“…Overexpressed LSD1 in cancer cells promotes glucose uptake and glycolytic activity and upregulates the expression of GLUT1 and glycolytic enzymes; however, it strongly downregulates the expression of mitochondrial metabolism-related genes (Luo et al, 2021). Knockdown or pharmacological inhibition of LSD1 can activate the transcriptional activity of the gluconeogenesis genes FBP1 and G6Pase, resulting in increased de novo glucose synthesis and decreased intracellular glycogen content (Wang D. et al, 2022). Inhibition of LSD1 activity in oesophageal cancer cells can significantly reduce the extracellular acidification rate (ECAR) and increase the oxygen consumption rate (OCR) and OCR/ECAR ratio (Kosumi et al, 2016).…”

Section: Energy Metabolism Pathwaymentioning

confidence: 99%

“…LSD1 may contribute to the malignant behaviour of oesophageal cancer by regulating metabolism, glycolytic pathway, and mitochondrial respiration. In addition, LSD1 plays an important role in regulating adaptive thermogenesis and lipid metabolism and may be a novel target for treating obesity (Wang D. et al, 2022).…”

Section: Energy Metabolism Pathwaymentioning

confidence: 99%

Mechanisms of carcinogenic activity triggered by lysine-specific demethylase 1A

Yang

Zang

et al. 2022

Front. Pharmacol.

Epigenetics has emerged as a prime focus area in the field of cancer research. Lysine-specific demethylase 1A (LSD1), the first discovered histone demethylase, is mainly responsible for catalysing demethylation of histone 3 lysine 4 (H3K4) and H3K9 to activate or inhibit gene transcription. LSD1 is abnormally expressed in various cancers and participates in cancer proliferation, apoptosis, metastasis, invasion, drug resistance and other processes by interacting with regulatory factors. Therefore, it may serve as a potential therapeutic target for cancer. This review summarises the major oncogenic mechanisms mediated by LSD1 and provides a reference for developing novel and efficient anticancer strategies targeting LSD1.