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p53 mdm2

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https://www.readbyqxmd.com/read/28732184/high-throughput-identification-of-mir-596-inducing-p53-mediated-apoptosis-in-hela-and-hct116-cells-using-cell-microarray
#1
Ming Ma, Junyu Yang, Bolun Wang, Zhihua Zhao, Jianzhong Jeff Xi
miRNAs play a key role in the regulation of gene networks in mammalian cells. However, little is known about their roles and functions in the apoptosis pathway. Here, we conducted a whole-genome miRNA screening for apoptosis and identified more than 100 miRNAs as apoptosis inducers. To further explain the roles of these mRNAs in apoptosis, a second round of screening was conducted between p53 +/+ and -/- cells. Among the hits, miR-596 was identified as a regulator of p53. The overexpression of miR-596 significantly increased p53 at the protein level, thereby inducing apoptosis...
July 1, 2017: SLAS Technology
https://www.readbyqxmd.com/read/28723868/screening-of-medicinal-plant-phytochemicals-as-natural-antagonists-of-p53-mdm2-interaction-to-reactivate-p53-functioning
#2
Muhammad Riaz, Usman A Ashfaq, Muhammad Qasim, Erum Yasmeen, Muhammad T Ul Qamar, Farooq Anwar
In most types of cancer, overexpression of murine double minute 2 (MDM2) often leads to inactivation of p53. The crystal structure of MDM2, with a 109-residue amino-terminal domain, reveals that MDM2 has a core hydrophobic region to which p53 binds as an amphipathic α helix. The interface depends on the steric complementarity between MDM2 and the hydrophobic region of p53. Especially, on p53's triad, amino acids Phe19, Trp23 and Leu26 bind to the MDM2 core. Results from studies suggest that the structural motif of both p53 and MDM2 can be attributed to similarities in the amphipathic α helix...
July 18, 2017: Anti-cancer Drugs
https://www.readbyqxmd.com/read/28723622/dual-targeting-of-mdm2-and-bcl2-as-a-therapeutic-strategy-in-neuroblastoma
#3
Alan Van Goethem, Nurten Yigit, Myrthala Moreno-Smith, Sanjeev A Vasudevan, Eveline Barbieri, Frank Speleman, Jason Shohet, Jo Vandesompele, Tom Van Maerken
Wild-type p53 tumor suppressor activity in neuroblastoma tumors is hampered by increased MDM2 activity, making selective MDM2 antagonists an attractive therapeutic strategy for this childhood malignancy. Since monotherapy in cancer is generally not providing long-lasting clinical responses, we here aimed to identify small molecule drugs that synergize with idasanutlin (RG7388). To this purpose we evaluated 15 targeted drugs in combination with idasanutlin in three p53 wild type neuroblastoma cell lines and identified the BCL2 inhibitor venetoclax (ABT-199) as a promising interaction partner...
July 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28722511/grwd1-a-new-player-among-oncogenesis-related-ribosomal-nucleolar-proteins
#4
Takuya Takafuji, Kota Kayama, Nozomi Sugimoto, Masatoshi Fujita
Increasing attention has been paid to certain ribosomal or ribosome biosynthesis-related proteins involved in oncogenesis. Members of one group are classified as "tumor suppressive factors" represented by RPL5 and RPL11; loss of their functions leads to cancer predisposition. RPL5 and RPL11 prevent tumorigenesis by binding to and inhibiting the MDM2 ubiquitin ligase and thereby up-regulating p53. Many other candidate tumor suppressive ribosomal/nucleolar proteins have been suggested. However, it remains to be experimentally clarified whether many of these factors can actually prevent tumorigenesis and if so, how they do so...
July 19, 2017: Cell Cycle
https://www.readbyqxmd.com/read/28721806/l-tetrahydropalmatine-induces-apoptosis-in-eu-4-leukemia-cells-by-down-regulating-x-linked-inhibitor-of-apoptosis-protein-and-increases-the-sensitivity-towards-doxorubicin
#5
S Li, D Chen, Renzhi Pei, Y Lu, P Zhang, J Ma, X Liu, X Du, K Sha, L Chen, J Cao, X Zhuang, J Wu, L Li, Z Fan, P Ye, S Tang, B Zhang, X Shi, K Li
BACKGROUND: L-Tetrahydropalmatine (L-THP) is a tetra-hydro protoberberine isoquinoline alkaloid. The phyto-compounds bearing isoquinoline alkaloids have been reported to show a potential effect against a number of human cancers cell lines including leukemia. We hypothesized that L-THP, being an isoquinoline alkaloid, could be a potential molecule against acute lymphoblastic leukemia (ALL), in this study, we evaluate L-THP against p53 deficient leukemia EU-4 cell lines in vitro. METHODS: For the study, p53 null leukemia EU-4 cells were used and treated with L-THP...
July 18, 2017: Current Molecular Medicine
https://www.readbyqxmd.com/read/28714398/nutlin-3-a-p53-mdm2-antagonist-for-nasopharyngeal-carcinoma-treatment
#6
Voon Yee-Lin, Wong Pooi-Fong, Alan Khoo Soo-Beng
Nasopharyngeal carcinoma (NPC) is a form of head and neck cancer of multifactorial etiologies that is highly prevalent among men in the populations of Southern China and Southeast Asia. NPC has claimed many thousands of lives worldwide; but the low awareness of NPC remains a hindrance in early diagnosis and prevention of the disease. NPC is highly responsive to radiotherapy and chemotherapy, but radiocurable NPC is still dependent on concurrent treatment of megavoltage radiotherapy with chemotherapy. Despite a significant reduction in loco-regional and distant metastases, radiotherapy alone has failed to provide a significant improvement in the overall survival rate of NPC, compared to chemotherapy...
July 17, 2017: Mini Reviews in Medicinal Chemistry
https://www.readbyqxmd.com/read/28712389/rescuing-p53-from-mdm2-by-intrinsically-unfolded-sumo-protease-4
#7
Do-Hyoung Kim, Chewook Lee, Bom Kim, Si-Hyung Lee, Kyou-Hoon Han
Many intrinsically unstructured/unfolded proteins (IUPs) contain transient local secondary structures even though they are "unstructured" in a tertiary sense. These local secondary structures are named "pre-structured motifs (PreSMos)" and in fact are the specificity determinants for IUP-target binding, i.e., the active sites in IUPs. Using high-resolution NMR we have delineated a PreSMo active site in the intrinsically unfolded mid-domain (residues 201-300) of SUMO-specific protease 4 (SUSP4). This 29-residue motif which we termed a p53 rescue motif can protect p53 from mdm2 quenching by binding to the p53-helix binding pocket in mdm2(3-109)...
July 17, 2017: BMB Reports
https://www.readbyqxmd.com/read/28707667/-the-activity-of-proapoptotic-genes-increases-after-renal-ischemia-reperfusion
#8
O I Kit, D I Vodolazhsky, S N Dimitriadi, D S Kutilin, N N Timoshkina, E N Gudueva, E M Frantsiyants
According to the World Health Organization, pathologies associated with ischemia/reperfusion occupy the leading position in the structure of mortality. The efficiency of localized kidney cancer surgery is limited by the damaging effects of prolonged warm ischemia and reperfusion. Ischemia/reperfusion damage to renal tissue may be related to changes in the expression profiles of pro- and antiapoptotic genes. Here, we have presented the longitudinal expression profiles of apoptosis-related genes in tissues of left and right (intact) kidneys of male rats exposed to unilateral ischemia followed by reperfusion...
May 2017: Molekuliarnaia Biologiia
https://www.readbyqxmd.com/read/28699903/molecular-chaperones-in-the-acquisition-of-cancer-cell-chemoresistance-with-mutated-tp53-and-mdm2-up-regulation
#9
Zuzanna Tracz-Gaszewska, Marta Klimczak, Przemyslaw Biecek, Marcin Herok, Marcin Kosinski, Maciej B Olszewski, Patrycja Czerwińska, Milena Wiech, Maciej Wiznerowicz, Alicja Zylicz, Maciej Zylicz, Bartosz Wawrzynow
Utilizing the TCGA PANCAN12 dataset we discovered that cancer patients with mutations in TP53 tumor suppressor and overexpression of MDM2 oncogene exhibited decreased survival post treatment. Interestingly, in the case of breast cancer patients, this phenomenon correlated with high expression level of several molecular chaperones belonging to the HSPA, DNAJB and HSPC families. To verify the hypothesis that such a genetic background may promote chaperone-mediated chemoresistance, we employed breast and lung cancer cell lines that constitutively overexpressed heat shock proteins and have shown that HSPA1A/HSP70 and DNAJB1/HSP40 facilitated the binding of mutated p53 to the TAp73α protein...
June 30, 2017: Oncotarget
https://www.readbyqxmd.com/read/28696156/the-igf-1r-akt-pathway-has-opposing-effects-on-nutlin-3a-induced-apoptosis
#10
Batzaya Davaadelger, Ricardo E Perez, Yalu Zhou, Lei Duan, Steven Gitelis, Carl G Maki
Nutlin-3a is a small molecule MDM2 antagonist and potent activator of wild-type p53. Nutlin-3a disrupts MDM2 binding to p53, thus increasing p53 levels and allowing p53 to inhibit proliferation or induce cell death. Factors that control sensitivity to Nutlin-3a-induced apoptosis are incompletely understood. In this study we isolated cisplatin-resistant clones from MHM cells, an MDM2-amplified and p53 wild-type osteosarcoma cell line. Cisplatin resistance in these clones resulted in part from heightened activation of the IGF-1R/AKT pathway...
July 11, 2017: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/28692053/pre-45s-rrna-promotes-colon-cancer-and-is-associated-with-poor-survival-of-crc-patients
#11
H Tsoi, K C Lam, Y Dong, X Zhang, C K Lee, J Zhang, S C Ng, S S M Ng, S Zheng, Y Chen, J Fang, J Yu
One characteristic of cancer cells is the abnormally high rate of cell metabolism to sustain their enhanced proliferation. However, the behind mechanism of this phenomenon is still elusive. Here we find that enhanced precursor 45s ribosomal RNA (pre-45s rRNA) is one of the core mechanisms in promoting the pathogenesis of colorectal cancer (CRC). Pre-45s rRNA expression is significantly higher in primary CRC tumor tissues samples and cancer cell lines compared with the non-tumorous colon tissues, and is associated with tumor sizes...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28692049/mdm2-selectively-suppresses-dna-damage-arising-from-inhibition-of-topoisomerase-ii-independent-of-p53
#12
J C Senturk, S Bohlman, J J Manfredi
Mdm2 is often overexpressed in tumors that retain wild-type TP53 but may affect therapeutic response independently of p53. Herein is shown that tumor cells with MDM2 amplification are selectively resistant to treatment with topoisomerase II poisons but not other DNA damaging agents. Tumor cells that overexpress Mdm2 have reduced DNA double-strand breaks in response to doxorubicin or etoposide. This latter result is not due to altered drug uptake. The selective attenuation of DNA damage in response to these agents is dependent on both Mdm2 levels and an intact ubiquitin ligase function...
July 10, 2017: Oncogene
https://www.readbyqxmd.com/read/28691783/two-steps-towards-complex-and-artificial-medium-and-macrocycles
#13
Alexander Doemling, Rudrakshula Madhavachary, Eman M M Abdelraheem, Arianna Rossetti, Aleksandra Twarda-Clapa, Bogdan Musielak, Katarzyna Kurpiewska, Justyna Kalinowska-Tłuścik, Tad A Holak
The design and synthesis of head-to-tail linked artificial macrocycles using the Ugi-reaction has been developed. This synthetic approach in just two steps is unprecedented short, efficient and works over a wide range of medium and macrocyclic loop sizes. The substrate scope and functional group tolerance is exceptional. Using this approach, we have synthesized 39 novel macrocycles including for example tylosin and we incorporate glycosylated macrocycles as well by two or even one single synthetic operation...
July 10, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28690977/regulation-of-the-mdm2-p53-signaling-axis-in-the-dna-damage-response-and-tumorigenesis
#14
Michael I Carr, Stephen N Jones
The p53 tumor suppressor acts as a guardian of the genome in mammalian cells undergoing DNA double strand breaks induced by a various forms of cell stress, including inappropriate growth signals or ionizing radiation. Following damage, p53 protein levels become greatly elevated in cells and p53 functions primarily as a transcription factor to regulate the expression a wide variety of genes that coordinate this DNA damage response. In cells undergoing high amounts of DNA damage, p53 can promote apoptosis, whereas in cells undergoing less damage, p53 promotes senescence or transient cell growth arrest and the expression of genes involved in DNA repair, depending upon the cell type and level of damage...
December 2016: Translational Cancer Research
https://www.readbyqxmd.com/read/28679301/tp53-in-adult-acute-lymphoblastic-leukemia
#15
Silvia Salmoiraghi, Alessandro Rambaldi, Orietta Spinelli
Acute lymphoblastic leukemia (ALL) is characterized by a great biological and clinical heterogeneity. Despite most adult patients enter complete hematologic remission after induction therapy only 40% survive five or more years. Over the last 20 years, the definition of an accurate biologic leukemia profile and the minimal residual disease evaluation in addition to conventional risk criteria led to a significant improvement for the risk stratification. The alterations of the oncosuppressor gene TP53, including deletions, sequence mutations and defect in its expression due to regulatory defects, define a new important predictor of adverse outcome...
July 6, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28679225/control-of-birhythmicity-a-self-feedback-approach
#16
Debabrata Biswas, Tanmoy Banerjee, Jürgen Kurths
Birhythmicity occurs in many natural and artificial systems. In this paper, we propose a self-feedback scheme to control birhythmicity. To establish the efficacy and generality of the proposed control scheme, we apply it on three birhythmic oscillators from diverse fields of natural science, namely, an energy harvesting system, the p53-Mdm2 network for protein genesis (the OAK model), and a glycolysis model (modified Decroly-Goldbeter model). Using the harmonic decomposition technique and energy balance method, we derive the analytical conditions for the control of birhythmicity...
June 2017: Chaos
https://www.readbyqxmd.com/read/28678832/association-of-mdm2-expression-with-shorter-progression-free-survival-and-overall-survival-in-patients-with-advanced-pancreatic-cancer-treated-with-gemcitabine-based-chemotherapy
#17
Shih-Hung Yang, Jen-Chieh Lee, Jhe-Cyuan Guo, Sung-Hsin Kuo, Yu-Wen Tien, Ting-Chun Kuo, Ann-Lii Cheng, Kun-Huei Yeh
This study evaluated the prognostic roles of murine double minute 2 (MDM2) and p53 in pancreatic cancer patients treated with gemcitabine-based chemotherapy. A total of 137 advanced or recurrent adenocarcinoma patients who were treated with gemcitabine-based palliative chemotherapy were reviewed, selected from 957 patients with pancreatic malignancy between 2008 and 2013 at our hospital. Immunohistochemical staining for MDM2 and p53 with formalin-fixed, paraffin-embedded tumor tissues was independently reviewed...
2017: PloS One
https://www.readbyqxmd.com/read/28673313/mdm2-x-inhibitors-under-clinical-evaluation-perspectives-for-the-management-of-hematological-malignancies-and-pediatric-cancer
#18
REVIEW
Veronica Tisato, Rebecca Voltan, Arianna Gonelli, Paola Secchiero, Giorgio Zauli
The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed...
July 3, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/28669344/p53-mdm2-interaction-inhibitors-as-novel-nongenotoxic-anticancer-agents
#19
Surendra Kumar Nayak, Gopal L Khatik, Rakesh Narang, Vikramdeep Monga, Harish Kumar Chopra
BACKGROUND: Cancer is a major global health problem with high mortality rate. Most of clinically used anticancer agents induce apoptosis through genotoxic stress at various stages of cell cycle and activation of p53. Acting as a tumor suppressor p53 plays a vital role in preventing tumor development. Tumor suppressor function of p53 is effectively antagonized by its direct interaction with murine double minute 2 (Mdm2) proteins via multiple mechanisms. Thus, p53-Mdm2 interaction has been found to be an important target for the development of novel anticancer agents...
June 23, 2017: Current Cancer Drug Targets
https://www.readbyqxmd.com/read/28663058/the-induction-of-tumour-suppressor-protein-p53-limits-the-entry-of-cells-into-the-pluripotent-inner-cell-mass-lineage-in-the-mouse-embryo
#20
L Ganeshan, X L Jin, C O'Neill
The early preimplantation embryo is susceptible to a range of exogenous stresses which result in their reduced long-term developmental potential. The P53 tumour suppressor protein is normally held at low levels in the preimplantation embryo and we show that culture stress induces the expression of a range of canonical P53-response genes (Mdm2, Bax and Cdkn1a). Culture stress caused a P53-dependent loss of cells from resulting blastocysts, and this was most evident within the inner cell mass population. Culture stress increased the proportion of cells expressing active caspase-3 and undergoing apoptosis, while inhibition of caspase-3 increased the number of cells within the inner cell mass...
June 26, 2017: Experimental Cell Research
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