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Regulating tumor suppressor genes: post-translational modifications.
Chen, L, Liu, S, Tao, Y
Signal transduction and targeted therapy. 2020;(1):90
Abstract
Tumor suppressor genes cooperate with each other in tumors. Three important tumor suppressor proteins, retinoblastoma (Rb), p53, phosphatase, and tensin homolog deleted on chromosome ten (PTEN) are functionally associated and they regulated by post-translational modification (PTMs) as well. PTMs include phosphorylation, SUMOylation, acetylation, and other novel modifications becoming growing appreciated. Because most of PTMs are reversible, normal cells use them as a switch to control the state of cells being the resting or proliferating, and PTMs also involve in cell survival and cell cycle, which may lead to abnormal proliferation and tumorigenesis. Although a lot of studies focus on the importance of each kind of PTM, further discoveries shows that tumor suppressor genes (TSGs) form a complex "network" by the interaction of modification. Recently, there are several promising strategies for TSGs for they change more frequently than carcinogenic genes in cancers. We here review the necessity, characteristics, and mechanisms of each kind of post-translational modification on Rb, p53, PTEN, and its influence on the precise and selective function. We also discuss the current antitumoral therapies of Rb, p53 and PTEN as predictive, prognostic, and therapeutic target in cancer.
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p53 tumor suppressor and iron homeostasis.
Zhang, J, Chen, X
The FEBS journal. 2019;(4):620-629
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Abstract
Iron is an essential nutrient for all living organisms and plays a vital role in many fundamental biochemical processes, such as oxygen transport, energy metabolism, and DNA synthesis. Due to its capability to produce free radicals, iron has deleterious effects and thus, its level needs to be tightly controlled in the body. Deregulation of iron metabolism is known to cause diseases, including anemia by iron deficiency and hereditary hemochromatosis by iron overload. Interestingly, dysregulated iron metabolism occurs frequently in tumor cells and contributes to tumorigenesis. In this review, we will discuss the role of p53 tumor suppressor in iron homeostasis.
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p53: key conductor of all anti-acne therapies.
Melnik, BC
Journal of translational medicine. 2017;(1):195
Abstract
This review based on translational research predicts that the transcription factor p53 is the key effector of all anti-acne therapies. All-trans retinoic acid (ATRA) and isotretinoin (13-cis retinoic acid) enhance p53 expression. Tetracyclines and macrolides via inhibiting p450 enzymes attenuate ATRA degradation, thereby increase p53. Benzoyl peroxide and hydrogen peroxide elicit oxidative stress, which upregulates p53. Azelaic acid leads to mitochondrial damage associated with increased release of reactive oxygen species inducing p53. p53 inhibits the expression of androgen receptor and IGF-1 receptor, and induces the expression of IGF binding protein 3. p53 induces FoxO1, FoxO3, p21 and sestrin 1, sestrin 2, and tumour necrosis factor-related apoptosis-inducing ligand (TRAIL), the key inducer of isotretinoin-mediated sebocyte apoptosis explaining isotretinoin's sebum-suppressive effect. Anti-androgens attenuate the expression of miRNA-125b, a key negative regulator of p53. It can thus be concluded that all anti-acne therapies have a common mode of action, i.e., upregulation of the guardian of the genome p53. Immortalized p53-inactivated sebocyte cultures are unfortunate models for studying acne pathogenesis and treatment.
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An integrative view on sex differences in brain tumors.
Sun, T, Plutynski, A, Ward, S, Rubin, JB
Cellular and molecular life sciences : CMLS. 2015;(17):3323-42
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Abstract
Sex differences in human health and disease can range from undetectable to profound. Differences in brain tumor rates and outcome are evident in males and females throughout the world and regardless of age. These observations indicate that fundamental aspects of sex determination can impact the biology of brain tumors. It is likely that optimal personalized approaches to the treatment of male and female brain tumor patients will require recognizing and understanding the ways in which the biology of their tumors can differ. It is our view that sex-specific approaches to brain tumor screening and care will be enhanced by rigorously documenting differences in brain tumor rates and outcomes in males and females, and understanding the developmental and evolutionary origins of sex differences. Here we offer such an integrative perspective on brain tumors. It is our intent to encourage the consideration of sex differences in clinical and basic scientific investigations.
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BRCA1 and p53 tumor suppressor molecules in Alzheimer's disease.
Nakanishi, A, Minami, A, Kitagishi, Y, Ogura, Y, Matsuda, S
International journal of molecular sciences. 2015;(2):2879-92
Abstract
Tumor suppressor molecules play a pivotal role in regulating DNA repair, cell proliferation, and cell death, which are also important processes in the pathogenesis of Alzheimer's disease. Alzheimer's disease is the most common neurodegenerative disorder, however, the precise molecular events that control the death of neuronal cells are unclear. Recently, a fundamental role for tumor suppressor molecules in regulating neurons in Alzheimer's disease was highlighted. Generally, onset of neurodegenerative diseases including Alzheimer's disease may be delayed with use of dietary neuro-protective agents against oxidative stresses. Studies suggest that dietary antioxidants are also beneficial for brain health in reducing disease-risk and in slowing down disease-progression. We summarize research advances in dietary regulation for the treatment of Alzheimer's disease with a focus on its modulatory roles in BRCA1 and p53 tumor suppressor expression, in support of further therapeutic research in this field.
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Transcriptome and Molecular Endocrinology Aspects of Epicardial Adipose Tissue in Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Observational Studies.
Maghbooli, Z, Hossein-Nezhad, A
BioMed research international. 2015;:926567
Abstract
The objective of this study was to perform a systematic review of published literature on differentially expressed genes (DEGs) in human epicardial adipose tissue (EAT) to identify molecules associated with CVDs. A systematic literature search was conducted in PubMed, SCOPUS, and ISI Web of Science literature databases for papers published before October 2014 that addressed EAT genes and cardiovascular diseases (CVDs). We included original papers that had performed gene expressions in EAT of patients undergoing open-heart surgery. The Reporting Recommendations for Tumor Marker Prognostic Studies (PRIMARK) assessment tool was also used for methodological quality assessment. From the 180 papers identified by our initial search strategy, 40 studies met the inclusion criteria and presented DEGs in EAT samples from patients with and without CVDs. The included studies reported 42 DEGs identified through comparison of EAT-specific gene expression in patients with and without CVDs. Among the 42 DEGs, genes involved in regulating apoptosis had higher enrichment scores. Notably, interleukin-6 (IL-6) and tumor protein p53 (TP53) were the main hub genes in the network. The results suggest that regulation of apoptosis in EAT is critical for CVD development. Moreover, IL-6 and TP53 as hub genes could serve as biomarkers and therapeutic targets for CVDs.
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The Role of TP53 Gene Codon 72 Polymorphism in Leukemia: A PRISMA-Compliant Systematic Review and Meta-Analysis.
Ruan, XL, Li, S, Meng, XY, Geng, P, Gao, QP, Ao, XB
Medicine. 2015;(38):e1588
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Abstract
The purpose of this meta-analysis was aimed to evaluate the association of tumor protein p53 (TP53) gene codon 72 polymorphism with leukemia susceptibility. We searched PubMed to identify relevant studies, and 16 case-control studies from 14 published articles were identified as eligible studies, including 2062 leukemia patients and 5826 controls. After extracting data, odds ratio (OR) with the corresponding 95% confidence interval (95%CI) was applied to assess the association between TP53 codon 72 polymorphism and leukemia susceptibility. The meta-analysis was performed with the Comprehensive Meta-Analysis software, version 2.2. Overall, no significant association between TP53 codon 72 polymorphism and leukemia susceptibility was found in this meta-analysis (Pro vs Arg: OR = 1.05, 95%CI = 0.90-1.21; Pro/Pro vs Arg/Arg: OR = 1.13, 95%CI = 0.84-1.52; Arg/Pro vs Arg/Arg: OR = 0.94, 95%CI = 0.76-1.15; [Pro/Pro + Arg/Pro] vs Arg/Arg: OR = 0.99, 95%CI = 0.80-1.21; Pro/Pro vs [Arg/Arg + Arg/Pro]: OR = 1.19, 95%CI = 0.93-1.51). Similar results were also found in subgroup analysis by ethnicity, source of controls, and types of leukemia (either acute myeloid leukemia or acute lymphocytic leukemia). Our meta-analysis demonstrates that TP53 codon 72 polymorphism may not be a risk factor for acute leukemia; however, due to the limitations of this study, it should be verified in future studies.
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p53 as an Effector or Inhibitor of Therapy Response.
Ablain, J, Poirot, B, Esnault, C, Lehmann-Che, J, de Thé, H
Cold Spring Harbor perspectives in medicine. 2015;(1):a026260
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Abstract
Although integrity of the p53 signaling pathway in a given tumor was expected to be a critical determinant of response to therapies, most clinical studies failed to link p53 status and treatment outcome. Here, we present two opposite situations: one in which p53 is an essential effector of cure by targeted leukemia therapies and another one in advanced breast cancers in which p53 inactivation is required for the clinical efficacy of dose-dense chemotherapy. If p53 promotes or blocks therapy response, therapies must be tailored on its status in individual tumors.
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The role of the apoptotic machinery in tumor suppression.
Delbridge, AR, Valente, LJ, Strasser, A
Cold Spring Harbor perspectives in biology. 2012;(11)
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Multicellular organisms have evolved processes to prevent abnormal proliferation or inappropriate tissue infiltration of cells, and these tumor suppressive mechanisms serve to prevent tissue hyperplasia, tumor development, and metastatic spread of tumors. These include potentially reversible processes such as cell cycle arrest and cellular senescence, as well as apoptotic cell death, which in contrast eliminates dangerous cells that may initiate tumor development. Tumor suppressive processes are organized as complex, extensive signaling networks, controlled by central "nodes." These "nodes" are prominent tumor suppressors, such as P53 or PTEN, whose loss is responsible for the development of the majority of human cancers. In this review we discuss the processes by which some of these prominent tumor suppressors trigger apoptotic cell death and how this process protects us from cancer development.
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Apoptosis in heart failure. -The role of the β-adrenergic receptor-mediated signaling pathway and p53-mediated signaling pathway in the apoptosis of cardiomyocytes-.
Fujita, T, Ishikawa, Y
Circulation journal : official journal of the Japanese Circulation Society. 2011;(8):1811-8
Abstract
The heart works as a driving force to deliver oxygen and nutrients to the whole body. Interrupting this function for only several minutes can cause critical and permanent damage to the human body. Thus, heart failure (HF) or attenuated cardiac function is an important factor that affects both patient's the quality of life and longevity. Numerous clinical and basic studies have been performed to clarify the complex pathophysiology of HF and to develop effective therapies. Modulating the β-adrenergic receptor-mediated signaling pathway has been one of the most crucial targets for HF therapy. Impressively, recent reports identified p53, a well-known tumor suppressor, as a major player in the development of HF. The present review highlights the apoptosis of cardiomyocytes, which is one of the important mechanisms that leads to HF and can be induced by both β-adrenergic signaling and p53. Consideration of the cross-talk among these major pathways will be important when developing effective and safe therapies for HF.