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p53 mdm2

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A p53-stapled peptide, ALRN-6924, blocks binding to MDMX and MDM2 to activate p53.
April 20, 2018: Cancer Discovery
Nilay Şen Türk, Saadettin Eskiçorapçi, Zafer Aybek, Levent Tuncay
Context: Urothelial carcinoma (UC) is one of the most frequent epithelial tumors worldwide. Aims: We aimed to investigate the protein expressions of caspase-8, p53, murine double minute 2 (mdm2), and p14ARF in nonmuscle UCs and to correlate the findings with clinicopathological characteristics. Settings and Design: A total of 50 patients who had pTa and pT1 tumors were analyzed. Subjects and Methods: The protein expressions of caspase-8, p53, mdm2, and p14ARF were analyzed by immunohistochemistry...
April 2018: Indian Journal of Pathology & Microbiology
Zhixue Du, Jing Yu, Fucai Li, Liyun Deng, Fang Wu, Xiangyi Huang, Jan Bergstrand, Jerker Widengren, Chaoqing Dong, Jicun Ren
Protein-protein interactions play a central role in signal transduction, transcription regulations, enzymatic activity and protein synthesis. The p53 protein is a key transcription factor and its activity is precisely regulated by p53-MDM2 interaction. Although p53-MDM2 interaction has been studied, it is still not clear about how p53 structures and external factors influence p53-MDM2 interaction in living cells. Here, we developed a direct method for monitoring the p53-MDM2 interaction in single living cells using single molecule fluorescence cross-correlation spectroscopy with a microfluidic chip...
April 19, 2018: Analytical Chemistry
Yuanfeng Zhou, Kuifeng Wang, Ni Zhou, Tingting Huang, Jiansheng Zhu, Jicheng Li
Introduction: In this study, we aimed to investigate the effect of butein on p53 in hepatocellular carcinoma (HCC) cells and the related molecular mechanisms by which p53 was activated. Methods: MTS assay and clonogenic survival assay were used to examine the antitumor activity of butein in vitro. Reporter gene assay was adopted to evaluate p53 transcriptional activity. Flow cytometry and western blotting were performed to study apoptosis induction and protein expression respectively...
2018: OncoTargets and Therapy
Halina Lisowska, Lei Cheng, Alice Sollazzo, Lovisa Lundholm, Aneta Wegierek-Ciuk, Sylwester Sommer, Anna Lankoff, Andrzej Wojcik
PURPOSE: Low temperature at exposure has been shown to act in a radioprotective manner at the level of cytogenetic damage. It was suggested to be due to an effective transformation of DNA damage to chromosomal damage at low temperature. The purpose of the study was to analyse the kinetics of aberration formation during the first hours after exposing human peripheral blood lymphocytes to ionising radiation at 0.8 °C and 37 °C. MATERIALS AND METHODS: To this end we applied the technique of premature chromosome condensation...
April 18, 2018: International Journal of Radiation Biology
Aram Ko, Su Yeon Han, Jaewhan Song
ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the ARF gene is a frequent target of genetic and epigenetic alterations including promoter hypermethylation or gene deletion...
April 18, 2018: Molecules and Cells
Alpana Mathur, Vivek Kumar Pandey, Poonam Kakkar
NF-E2 p45-related factor 2 (Nrf2), is a major redox sensitive transcription factor that plays an essential role in regulating glucose metabolism. Inactivation of Nrf2 has been associated with diabetic complications however, mechanisms warranting Nrf2 suppression are incompletely understood. We hypothesized that PHLPP1 activates GSK3β to induce β-TrCP mediated Nrf2 phosphorylation and degradation. In vivo study was carried out in STZ-NA induced type 2 diabetic male Wistar rats. GSK3β mediated Nrf2 ubiquitination was confirmed by administration of GSK3β inhibitor (LiCl; 60mg/kg bwt...
April 12, 2018: Free Radical Biology & Medicine
Shing-Jyh Chang, En-Chi Liao, Hsin-Yueh Yeo, Wen-Hong Kuo, Hsin-Yi Chen, Yi-Ting Tsai, Yu-Shan Wei, Ying-Jen Chen, Yi-Shiuan Wang, Ji-Min Li, Chuan-Chi Shih, Chia-Hao Chan, Hsiu-Chuan Chou, Yung-Jen Chuang, Hong-Lin Chan
With the concept of precision medicine, combining multiple molecular-targeting therapies has brought new approaches to current cancer treatments. Malfunction of the tumor suppressor protein, p53 is a universal hallmark in human cancers. Under normal conditions, p53 is degraded through an ubiquitin-proteosome pathway regulated by its negative regulator, MDM2. In contrast, cellular stress such as DNA damage will activate p53 to carry out DNA repair, cell cycle arrest, and apoptosis. In this study, we focused on ovarian carcinoma with high EGFR and MDM2 overexpression rate...
April 12, 2018: Archives of Biochemistry and Biophysics
Luis A Carvajal, Daniela Ben Neriah, Adrien Senecal, Lumie Benard, Victor Thiruthuvanathan, Tatyana Yatsenko, Swathi-Rao Narayanagari, Justin C Wheat, Tihomira I Todorova, Kelly Mitchell, Charles Kenworthy, Vincent Guerlavais, D Allen Annis, Boris Bartholdy, Britta Will, Jesus D Anampa, Ioannis Mantzaris, Manuel Aivado, Robert H Singer, Robert A Coleman, Amit Verma, Ulrich Steidl
The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX...
April 11, 2018: Science Translational Medicine
Theodoros Karantanos, Alison R Moliterno
The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN...
March 30, 2018: Blood Reviews
Omid Tavana, Hongbin Sun, Wei Gu
Inhibition of Mdm2 function is a validated approach to restore p53 activity for cancer therapy; nevertheless, inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway need to be further elucidated. Our finding that the Herpesvirus-Associated Ubiquitin-Specific Protease (HAUSP, also called USP7) interacts with the p53/Mdm2 protein complex, was one of the first examples that deubiquitinases (DUBs) exhibit a specific role in regulating protein stability. Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53-dependent apoptosis in human cancer cells...
April 4, 2018: Cell Cycle
Zhenbiao Zhang, Dandan Luo, Jianhui Xie, Guosheng Lin, Jiangtao Zhou, Weihai Liu, Huilin Li, Tiegang Yi, Ziren Su, Jianping Chen
The biological activity of curcumin (CUR), a promising naturally occurring dietary compound for the treatment of hepatocellular carcinoma (HCC), was closely associated with its metabolite. Octahydrocurcumin (OHC) is the final hydrogenated metabolite of CUR and has been reported to have potential biological activities. However, difficulties in access have hampered its biological studies. In the current investigation, we designed an efficient synthesis method to produce OHC, and comparatively explored the anti-cancer effect and potential mechanism of OHC and CUR in an H22 ascites tumor-bearing mice model...
April 4, 2018: Food & Function
Fang-Fang He, Ren-Yu You, Chen Ye, Chun-Tao Lei, Hui Tang, Hua Su, Chun Zhang
BACKGROUND/AIMS: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD+-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. METHODS: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice...
March 26, 2018: Cellular Physiology and Biochemistry
Arghavan Bahadorinejad, Ulisses M Braga-Neto
We propose a methodology for model-based fault detection and diagnosis for stochastic Boolean dynamical systems indirectly observed through a single time series of transcriptomic measurements using Next Generation Sequencing (NGS) data. The fault detection consists of an innovations filter followed by a fault certification step, and requires no knowledge about the possible system faults. The innovations filter uses the optimal Boolean state estimator, called the Boolean Kalman Filter (BKF). In the presence of knowledge about the possible system faults, we propose an additional step of fault diagnosis based on a multiple model adaptive estimation (MMAE) method consisting of a bank of BKFs running in parallel...
March 2018: IEEE/ACM Transactions on Computational Biology and Bioinformatics
Jie Liu, Cao Zhang, Huailing Wang, Lei Zhang, Zhenlei Jiang, Jianrun Zhang, Zhijun Liu, Heru Chen
Fifty 1,3-dioxyxanthone nitrates (4a ∼ i-n, n = 1-6) were designed and synthesized based on molecular similarity strategy. Incorporation of nitrate into 1,3-dioxyxanthones with electron-donating groups at 6-8 position brought about synergistic anticancer effect. Among them, compound 4g-4 was confirmed the most active agent against HepG-2 cells growth with an IC50 of 0.33 ± 0.06 μM. It dose-dependently increased intramolecular NO levels. This activity was attenuated by either NO scavenger PTIO or mitochondrial aldehyde dehydrogenase (mtADH) inhibitor PCDA...
March 27, 2018: European Journal of Medicinal Chemistry
Silvia Romano, Annalisa Lamberti, Mariorosario Masullo, Erika Penzo, Stefano Cabrini, Ivo Rendina, Vito Mocella
A novel optical label-free bio-sensing platform based on a new class of resonances supported in a photonic crystal metasurface is reported herein. Molecular binding is detected as a shift in the resonant wavelength of the bound states in the continuum of radiation modes. The new configuration is applied to the recognition of the interaction between protein p53 and its protein regulatory partner murine double minute 2 (MDM2). A detection limit of 66 nM for the protein p53 is found. The device provides an excellent interrogation stability and loss-free operation, requires minimal optical interrogation equipment and can be easily optimized to work in a wide wavelength range...
March 30, 2018: Materials
K R Patel, B N Vajaria, R D Singh, R Begum, P S Patel
p53 plays a central role in prevention of normal cell from the development of the malignant phenotype. Somatic alterations (mutations, loss of heterozygosity, deletions) in p53 are a hallmark of most human cancers and cause defects in normal p53 function. However, in the tumors harboring wild-type p53, there are alterations in the regulation of the p53. Thus, understanding why p53 is unable to perform its role as a tumor suppressor in these wild-type tumors is very crucial. Germ-line polymorphisms in p53 are also anticipated to cause measurable disturbance in p53 function...
March 2018: Experimental Oncology
R C Heijkants, M Nieveen, K C 't Hart, A F A S Teunisse, A G Jochemsen
Uveal melanoma (UM) is the most frequent ocular cancer in adults, accounting for ~5% of the total melanoma incidence. Although the primary tumor is well treatable, patients frequently develop metastases for which no curative therapy exists. Highly activated protein kinase C (PKC) is a common feature of UM and has shown potential as therapeutic intervention for UM patients. Unfortunately, PKC inhibition as single treatment appears to have only limited clinical benefit. Combining PKC inhibition with activation of p53, which is rarely mutated in UM, by MDM2 inhibitors has shown promising results in vitro and in vivo...
March 29, 2018: Oncogenesis
Samy A Azer
Human hepatocellular carcinoma (HCC) is the fifth most common cancer and is associated with poor prognosis worldwide. The molecular mechanisms underlying the pathogenesis of HCC have been an area of continuing interest, and recent studies using next generation sequencing (NGS) have revealed much regarding previously unsettled issues. Molecular studies using HCC samples have been mainly targeted with the aim to identify the fundamental mechanisms contributing to HCC and identify more effective treatments. In response to cellular stresses (e...
March 27, 2018: Journal of Clinical Medicine
Qingling Huang, Lihong Chen, Leixiang Yang, Xiaoling Xie, Lin Gan, John L Cleveland, Jiandong Chen
The MDM2 homolog MDMX oncoprotein is indispensable for inhibition of p53 during normal embryonic development and malignant transformation, yet how MDMX harnesses p53 functions is unclear. In addition to a canonical N-terminal p53-binding domain, recent work suggests the central acidic domain of MDMX regulates p53 interaction through intramolecular mimicry and engages in second-site interaction with the p53 core domain in vitro. To test the physiological relevance of these interactions, we generated an MDMX knockin mouse having substitutions in a conserved WW motif necessary for these functions (W201S/W202G)...
March 26, 2018: Proceedings of the National Academy of Sciences of the United States of America
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