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https://www.readbyqxmd.com/read/28617332/dynamic-allostery-modulates-catalytic-activity-by-modifying-the-hydrogen-bonding-network-in-the-catalytic-site-of-human-pin1
#1
Jing Wang, Ryosuke Kawasaki, Jun-Ichi Uewaki, Arif U R Rashid, Naoya Tochio, Shin-Ichi Tate
Allosteric communication among domains in modular proteins consisting of flexibly linked domains with complimentary roles remains poorly understood. To understand how complementary domains communicate, we have studied human Pin1, a representative modular protein with two domains mutually tethered by a flexible linker: a WW domain for substrate recognition and a peptidyl-prolyl isomerase (PPIase) domain. Previous studies of Pin1 showed that physical contact between the domains causes dynamic allostery by reducing conformation dynamics in the catalytic domain, which compensates for the entropy costs of substrate binding to the catalytic site and thus increases catalytic activity...
June 15, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28617078/interplay-between-notch-and-p53-promotes-neuronal-cell-death-in-ischemic-stroke
#2
Priyanka Balaganapathy, Sang-Ha Baik, Karthik Mallilankaraman, Christopher G Sobey, Dong-Gyu Jo, Thiruma V Arumugam
Stroke is the world's second leading cause of mortality, with a high incidence of morbidity. Numerous neuronal membrane receptors are activated by endogenous ligands and may contribute to infarct development. Notch is a well-characterized membrane receptor involved in cell differentiation and proliferation, and now shown to play a pivotal role in cell death during ischemic stroke. Blockade of Notch signaling by inhibition of γ-secretase, an enzyme that generates the active form of Notch, is neuroprotective following stroke...
January 1, 2017: Journal of Cerebral Blood Flow and Metabolism
https://www.readbyqxmd.com/read/28598431/a-covalent-pin1-inhibitor-selectively-targets-cancer-cells-by-a-dual-mechanism-of-action
#3
Elena Campaner, Alessandra Rustighi, Alessandro Zannini, Alberto Cristiani, Silvano Piazza, Yari Ciani, Ori Kalid, Gali Golan, Erkan Baloglu, Sharon Shacham, Barbara Valsasina, Ulisse Cucchi, Agnese Chiara Pippione, Marco Lucio Lolli, Barbara Giabbai, Paola Storici, Paolo Carloni, Giulia Rossetti, Federica Benvenuti, Ezia Bello, Maurizio D'Incalci, Elisa Cappuzzello, Antonio Rosato, Giannino Del Sal
The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs...
June 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28592245/in-silico-identification-of-potential-key-regulatory-factors-in-smoking-induced-lung-cancer
#4
Salem A El-Aarag, Amal Mahmoud, Medhat H Hashem, Hatem Abd Elkader, Alaa E Hemeida, Mahmoud ElHefnawi
BACKGROUND: Lung cancer is a leading cause of cancer-related death worldwide and is the most commonly diagnosed cancer. Like other cancers, it is a complex and highly heterogeneous disease involving multiple signaling pathways. Identifying potential therapeutic targets is critical for the development of effective treatment strategies. METHODS: We used a systems biology approach to identify potential key regulatory factors in smoking-induced lung cancer. We first identified genes that were differentially expressed between smokers with normal lungs and those with cancerous lungs, then integrated these differentially expressed genes (DEGs) with data from a protein-protein interaction database to build a network model with functional modules for pathway analysis...
June 7, 2017: BMC Medical Genomics
https://www.readbyqxmd.com/read/28575401/localization-of-arabidopsis-forked1-to-a-raba-positive-compartment-suggests-a-role-in-secretion
#5
Neema Prabhakaran Mariyamma, Hongwei Hou, Francine M Carland, Timothy Nelson, Elizabeth A Schultz
When FORKED1 (FKD1) is mutated, asymmetric localization of PINFORMED1 (PIN1), particularly to the apical side of cells, fails to occur properly in developing veins, resulting in an open vein pattern. FKD1 encodes a protein with a Pleckstrin homology-like (PL) domain, suggesting interaction with phosphoinositides. FKD1 has been previously found to interact with an ADP ribosylation factor GTPase-activating protein (ARF-GAP) important for vein patterning, SCARFACE/VAN3 (SFC). We find that FKD1-green fluorescent protein (GFP) localizes to the plasma membrane and to punctae labeled by SFC-yellow fluorescent protein (YFP)...
June 1, 2017: Journal of Experimental Botany
https://www.readbyqxmd.com/read/28566287/the-prolyl-isomerase-pin1-increases-%C3%AE-cell-proliferation-and-enhances-insulin-secretion
#6
Yusuke Nakatsu, Keiichi Mori, Yasuka Matsunaga, Takeshi Yamamotoya, Koji Ueda, Yuki Inoue, Keiko Mitsuzaki-Miyoshi, Hideyuki Sakoda, Midori Fujishiro, Suguru Yamaguchi, Akifumi Kushiyama, Hiraku Ono, Hisamitsu Ishihara, Tomoichiro Asano
The prolyl isomerase Pin1 binds to the phosphorylated Ser/Thr-Pro motif of target proteins and enhances their cis-trans conversion. This report is the first to show that Pin1 expression in pancreatic β cells is markedly elevated by high-fat diet feeding and in ob/ob mice. To elucidate the role of Pin1 in pancreatic β cells, we generated β cell-specific Pin1 KO (βPin1 KO) mice. These mutant mice showed exacerbation of glucose intolerance but had normal insulin sensitivity. We identified two independent factors underlying impaired insulin secretion in the βPin1 KO mice...
May 31, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28556372/plant-plant-interactions-influence-developmental-phase-transitions-grain-productivity-and-root-system-architecture-in-arabidopsis-via-auxin-and-pft1-med25-signaling
#7
Edith Muñoz-Parra, Ramón Pelagio-Flores, Javier Raya-González, Guadalupe Salmerón-Barrera, León Francisco Ruiz-Herrera, Eduardo Valencia-Cantero, José López-Bucio
Transcriptional regulation of gene expression influences plant growth, environmental interactions, and plant-plant communication. Here, we report that population density is a key factor for plant productivity and a major root architectural determinant in Arabidopsis thaliana. When grown in soil at varied densities from 1 to 32 plants, high number of individuals decreased stem growth and accelerated senescence, which negatively correlated with total plant biomass and seed production at the completion of the life cycle...
May 27, 2017: Plant, Cell & Environment
https://www.readbyqxmd.com/read/28533744/pin1-modulates-huntingtin-levels-and-aggregate-accumulation-an-in-vitro-model
#8
Alisia Carnemolla, Silvia Michelazzi, Elena Agostoni
Huntington's disease (HD) is a dominantly inherited neurodegenerative disorder characterized by a polyglutamine expansion within the N-terminal region of huntingtin protein (HTT). Cellular mechanisms promoting mutant huntingtin (mHTT) clearance are of great interest in HD pathology as they can lower the level of the mutant protein and its toxic aggregated species, thus affecting disease onset and progression. We have previously shown that the prolyl-isomerase PIN1 represents a promising negative regulator of mHTT aggregate accumulation using a genetically precise HD mouse model, namely Hdh(Q111) mice...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28525371/arsenic-trioxide-and-angiotensin-ii-have-inhibitory-effects-on-herg-protein-expression-evidence-for-the-role-of-pml-sumoylation
#9
Yu Liu, Duo Li, Dan Nie, Shang-Kun Liu, Fang Qiu, Mei-Tong Liu, Yuan-Yuan Li, Jia-Xin Wang, Yan-Xin Liu, Chang-Jiang Dong, Di Wu, Wei Tian, Jia Yang, Wei Mu, Jia-Tong Li, Dan Zhao, Xiao-Feng Wang, Wen-Feng Chu, Bao-Feng Yang
The human ether-a-go-go-related gene (HERG) channel is a novel target for the treatment of drug-induced long QT syndrome, which causes lethal cardiotoxicity. This study is designed to explore the possible role of PML SUMOylation and its associated nuclear bodies (NBs) in the regulation of HERG protein expression. Both arsenic trioxide (ATO) and angiotensin II (Ang II) were able to significantly reduce HERG protein expression, while also increasing PML SUMOylation and accelerating the formation of PML-NBs. Pre-exposure of cardiomyocytes to a SUMOylation chemical inhibitor, ginkgolic acid, or the silencing of UBC9 suppressed PML SUMOylation, subsequently preventing the downregulation of HERG induced by ATO or Ang II...
May 2, 2017: Oncotarget
https://www.readbyqxmd.com/read/28517007/generation-of-a-cell-permeable-cycloheptapeptidyl-inhibitor-against-the-peptidyl-prolyl-isomerase-pin1
#10
Walaa Bedewy, Hui Liao, Nageh A Abou-Taleb, Sherif F Hammad, Tamer Nasr, Dehua Pei
Cyclic peptides are capable of binding and modulating challenging drug targets including protein-protein interactions. However, their lack of membrane permeability prevents their application against intracellular targets. In this study, we show that it is possible to design a cell-permeable and biologically active cycloheptapeptide inhibitor against the intracellular enzyme peptidyl-prolyl isomerase Pin1 by integrating cell-penetrating and target-binding sequences.
May 31, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28506742/investigation-of-gene-expression-and-serum-levels-of-pin1-and-enos-with-high-blood-pressure-in-patients-with-alzheimer-disease
#11
Mina Azimi, Masoud Nikanfar, Fatemeh Khakikhatibi, Reza Rahbarghazi, Seyed Manuchehr Nourazarian, Cigir Biray Avci, Alireza Nourazarian
According to evidence, Alzheimer's disease is known as one of the most serious neurodegenerative diseases, for which hypertension has been observed to be a key risk factor. Therefore, this study aims to examine the relationship between the PIN1 and eNOS genes expression, as well as serum levels and hypertension in Alzheimer's disease sufferers. Blood samples were obtained from subjects who were divided into four groups: the control group, normotensive Alzheimer's patients, the Alzheimer's sufferers group with hypertension, and the healthy group with only hypertension, considering the inhibition of confounding factors...
May 12, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28483911/cd99-derived-agonist-ligands-inhibit-fibronectin-induced-activation-of-%C3%AE-1-integrin-through-pka-shp2-erk-ptpn12-fak-signaling-pathway
#12
Kyoung-Jin Lee, Yuri Kim, Yeon Ho Yoo, Min-Seo Kim, Sun-Hee Lee, Chang-Gyum Kim, Kyeonghan Park, Dooil Jeoung, Hansoo Lee, In Young Ko, Jang-Hee Hahn
The human CD99 protein is a 32kDa glycosylated transmembrane protein that regulates various cellular responses including cell adhesion and leukocyte extravasation. We previously reported that CD99 activation suppresses β1 integrin activity through dephosphorylation of FAK at Y397. We explored a molecular mechanism underlying the suppression of β1 integrin activity by CD99 agonists and its relevance to tumor growth in vivo CD99-Fc fusion proteins or a series of CD99-derived peptides suppressed β1 integrin activity by specifically interacting with three conserved motifs of the CD99 extracellular domain...
May 8, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/28481868/prolyl-isomerase-pin1-regulates-the-stability-transcriptional-activity-and-oncogenic-potential-of-brd4
#13
X Hu, S-H Dong, J Chen, X Z Zhou, R Chen, S Nair, K P Lu, L-F Chen
BRD4 has emerged as an important factor in tumorigenesis by promoting the transcription of genes involved in cancer development. However, how BRD4 is regulated in cancer cells remains largely unknown. Here, we report that the stability and functions of BRD4 are positively regulated by prolyl isomerase PIN1 in gastric cancer cells. PIN1 directly binds to phosphorylated threonine (T) 204 of BRD4 as revealed by peptide binding and crystallographic studies and enhances BRD4's stability by inhibiting its ubiquitination...
May 8, 2017: Oncogene
https://www.readbyqxmd.com/read/28469131/transcription-factors-nf-ya2-and-nf-ya10-regulate-leaf-growth-via-auxin-signaling-in-arabidopsis
#14
Min Zhang, Xiaolong Hu, Ming Zhu, Miaoyun Xu, Lei Wang
In plants, leaf is crucial for photosynthesis and respiration. Leaf area and quantity are important for leaf vegetables to increase biomass. The process of leaf development involves coordinated regulation among small RNAs, transcription factors and hormones. Here, we found leaf size were regulated by transcription factors NF-YA2 and NF-YA10 in Arabidopsis. NF-YA2 and NF-YA10 overexpression increased biomass accumulation through promoting leaf growth and cell expansion. NF-YA2 and NF-YA10 were expressed in SAM and leaf vasculature...
May 3, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28458925/pathological-role-of-peptidyl-prolyl-isomerase-pin1-in-the-disruption-of-synaptic-plasticity-in-alzheimer-s-disease
#15
Lingyan Xu, Zhiyun Ren, Frances E Chow, Richard Tsai, Tongzheng Liu, Flavio Rizzolio, Silvia Boffo, Yungen Xu, Shaohui Huang, Carol F Lippa, Yuesong Gong
Synaptic loss is the structural basis for memory impairment in Alzheimer's disease (AD). While the underlying pathological mechanism remains elusive, it is known that misfolded proteins accumulate as β-amyloid (Aβ) plaques and hyperphosphorylated Tau tangles decades before the onset of clinical disease. The loss of Pin1 facilitates the formation of these misfolded proteins in AD. Pin1 protein controls cell-cycle progression and determines the fate of proteins by the ubiquitin proteasome system. The activity of the ubiquitin proteasome system directly affects the functional and structural plasticity of the synapse...
2017: Neural Plasticity
https://www.readbyqxmd.com/read/28453695/genetic-variants-of-dna-repair-related-genes-predict-efficacy-of-tas-102-in-patients-with-refractory-metastatic-colorectal-cancer
#16
M Suenaga, M Schirripa, S Cao, W Zhang, D Yang, S Murgioni, D Rossini, F Marmorino, A Mennitto, Y Ning, S Okazaki, M D Berger, Y Miyamoto, R Gopez, A Barzi, T Yamaguchi, F Loupakis, H-J Lenz
Background: Tri-phosphorylated trifluridine (FTD) incorporation into DNA is TAS-102's main anti-tumor action. We tested whether genetic polymorphisms in homologous recombination (HR) and cell cycle checkpoint pathway for DNA repair is associated with outcomes in refractory metastatic colorectal cancer (mCRC) patients treated with TAS-102. Patients and methods: We analyzed genomic DNA extracted from 233 samples of three cohorts: an evaluation cohort of 52 patients receiving TAS-102, a validation cohort of 129 patients receiving TAS-102 and a control cohort of 52 patients receiving regorafenib...
May 1, 2017: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/28431929/effects-of-naturally-occurring-charged-mutations-on-the-structure-stability-and-binding-of-the-pin1-ww-domain
#17
Xiaoya Qiao, Ying Liu, Liting Luo, Lei Chen, Caixian Zhao, Xuanjun Ai
Pin1 is a peptidyl-prolyl cis-trans isomerase, whose WW domain specifically recognizes the pSer/Thr-Pro motif. Pin1 is involved in multiple phosphorylation events that regulate the activities of various substrates, and Pin1 deregulation has been reported in various diseases, including cancer and Alzheimer's disease. The WW domain of Pin1 has been used as a small model protein to investigate the folding mechanisms of the β-sheet structure by studying the effect of mutations or its naturally occurring variants...
May 27, 2017: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/28426725/dynamic-regulation-of-pin1-expression-and-function-during-zebrafish-development
#18
Maria Solange Ibarra, Carla Borini Etichetti, Carolina Di Benedetto, Germán L Rosano, Ezequiel Margarit, Giannino Del Sal, Marina Mione, Javier Girardini
The prolyl isomerase Pin1 plays a key role in the modulation of proline-directed phosphorylation signaling by inducing local conformational changes in phosphorylated protein substrates. Extensive studies showed different roles for Pin1 in physiological processes and pathological conditions such as cancer and neurodegenerative diseases. However, there are still several unanswered questions regarding its biological role. Notably, despite evidences from cultured cells showing that Pin1 expression and activity may be regulated by different mechanisms, little is known on their relevance in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28411196/correction-senp1-desumoylates-and-regulates-pin1-protein-activity-and-cellular-function
#19
(no author information available yet)
No abstract text is available yet for this article.
April 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28404959/inhibition-of-the-prolyl-isomerase-pin1-enhances-the-ability-of-sorafenib-to-induce-cell-death-and-inhibit-tumor-growth-in-hepatocellular-carcinoma
#20
Min Zheng, Huijuan Xu, Xin-Hua Liao, Champ Peng Chen, Arina Li Zhang, Wenxian Lu, Long Wang, Dayun Yang, Jichuang Wang, Hekun Liu, Xiao Zhen Zhou, Kun Ping Lu
Hepatocellular carcinoma (HCC) is the sixth most common cancer, but is the second leading cause of cancer deaths, partially due to its heterogeneity and drug resistance. Sorafenib is the only medical treatment with a proven efficacy against advanced HCC, but its overall clinical efficacy is still modest. Therefore, a major challenge is how to improve its therapeutic efficacy. The unique prolyl isomerase Pin1 regulates numerous cancer-driving pathways. Notably, Pin1 is overexpressed in about 70% HBV-positive HCC patients and contributes to HCC tumorigenesis...
May 2, 2017: Oncotarget
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