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71.
Xiangli Cui Erin E. Witalison Alena P. Chumanevich Alexander A. Chumanevich Deepak Poudyal Venkataraman Subramanian Aaron J. Schetter Curtis C. Harris Paul R. Thompson Lorne J. Hofseth 《PloS one》2013,8(1)
Protein Arginine Deiminases (PADs) catalyze the post-translational conversion of peptidyl-Arginine to peptidyl-Citrulline in a calcium-dependent, irreversible reaction. Evidence is emerging that PADs play a role in carcinogenesis. To determine the cancer-associated functional implications of PADs, we designed a small molecule PAD inhibitor (called Chor-amidine or Cl-amidine), and tested the impact of this drug on the cell cycle. Data derived from experiments in colon cancer cells indicate that Cl-amidine causes a G1 arrest, and that this was p53-dependent. In a separate set of experiments, we found that Cl-amidine caused a significant increase in microRNA-16 (miRNA-16), and that this increase was also p53-dependent. Because miRNA-16 is a putative tumor suppressor miRNA, and others have found that miRNA-16 suppresses proliferation, we hypothesized that the p53-dependent G1 arrest associated with PAD inhibition was, in turn, dependent on miRNA-16 expression. Results are consistent with this hypothesis. As well, we found the G1 arrest is at least in part due to the ability of Cl-amidine-mediated expression of miRNA-16 to suppress its'' G1-associated targets: cyclins D1, D2, D3, E1, and cdk6. Our study sheds light into the mechanisms by which PAD inhibition can protect against or treat colon cancer. 相似文献
72.
Isadore Budnick Emily Hamburg‐Shields Demeng Chen Eduardo Torre Andrew Jarrell Batool Akhtar‐Zaidi Olivia Cordovan Rob C. Spitale Peter Scacheri Radhika P. Atit 《Genesis (New York, N.Y. : 2000)》2016,54(8):415-430
Embryonic dermal fibroblasts in the skin have the exceptional ability to initiate hair follicle morphogenesis and contribute to scarless wound healing. Activation of the Wnt signaling pathway is critical for dermal fibroblast fate selection and hair follicle induction. In humans, mutations in Wnt pathway components and target genes lead to congenital focal dermal hypoplasias with diminished hair. The gene expression signature of embryonic dermal fibroblasts during differentiation and its dependence on Wnt signaling is unknown. Here we applied Shannon entropy analysis to identify the gene expression signature of mouse embryonic dermal fibroblasts. We used available human DNase‐seq and histone modification ChiP‐seq data on various cell‐types to demonstrate that genes in the fibroblast cell identity signature can be epigenetically repressed in other cell‐types. We found a subset of the signature genes whose expression is dependent on Wnt/β‐catenin activity in vivo. With our approach, we have defined and validated a statistically derived gene expression signature that may mediate dermal fibroblast identity and function in development and disease. genesis 54:415–430, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
73.
Diane C. Saunders Marcela Brissova Neil Phillips Shristi Shrestha John T. Walker Radhika Aramandla Greg Poffenberger David K. Flaherty Kevin P. Weller Julie Pelletier Tracy Cooper Matt T. Goff John Virostko Alena Shostak E. Danielle Dean Dale L. Greiner Leonard D. Shultz Nripesh Prasad Alvin C. Powers 《Cell metabolism》2019,29(3):745-754.e4
74.
75.
Biophysical characterization of anticoagulant hemextin AB complex from the venom of snake Hemachatus haemachatus
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Banerjee Y Lakshminarayanan R Vivekanandan S Anand GS Valiyaveettil S Kini RM 《Biophysical journal》2007,93(11):3963-3976
Hemextin AB complex from the venom of Hemachatus haemachatus is the first known natural anticoagulant that specifically inhibits the enzymatic activity of blood coagulation factor VIIa in the absence of factor Xa. It is also the only known heterotetrameric complex of two three-finger toxins. Individually only hemextin A has mild anticoagulant activity, whereas hemextin B is inactive. However, hemextin B synergistically enhances the anticoagulant activity of hemextin A and their complex exhibits potent anticoagulant activity. In this study we characterized the nature of molecular interactions leading to the complex formation. Circular dichroism studies indicate the stabilization of β-sheet in the complex. Hemextin AB complex has an increased apparent molecular diameter in both gas and liquid phase techniques. The complex formation is enthalpically favorable and entropically unfavorable with a negative change in the heat capacity. Thus, the anticoagulant complex shows less structural flexibility than individual subunits. Both electrostatic and hydrophobic interactions are important for the complexation; the former driving the process and the latter helping in the stabilization of the tetramer. The tetramer dissociates into dimers and monomers with the increase in the ionic strength of the solution and also with increase in the glycerol concentration in the buffer. The two dimers formed under each of these conditions display distinct differences in their apparent molecular diameters and anticoagulant properties. Based on these results, we have proposed a model for this unique anticoagulant complex. 相似文献
76.
Gale AJ Yegneswaran S Xu X Pellequer JL Griffin JH 《The Journal of biological chemistry》2007,282(30):21848-21855
Prothrombin is proteolytically activated by the prothrombinase complex comprising the serine protease Factor (F) Xa complexed with its cofactor, FVa. Based on inhibition of the prothrombinase complex by synthetic peptides, FVa residues 493-506 were proposed as a FXa binding site. FVa is homologous to FVIIIa, the cofactor for the FIXa protease, in the FX-activating complex, and FVIIIa residues 555-561 (homologous to FVa residues 499-506) are recognized as a FIXa binding sequence. To test the hypothesis that FVa residues 499-505 contribute to FXa binding, we created the FVa loop swap mutant (designated 499-505(VIII) FV) with residues 499-505 replaced by residues 555-561 of FVIIIa, which differ at five of seven positions. Based on kinetic measurements and spectroscopic titrations, this FVa loop swap mutant had significantly reduced affinity for FXa. The fully formed prothrombinase complex containing this FVa mutant had fairly normal kinetic parameters (k(cat) and K(m)) for cleavage of prothrombin at Arg-320. However, small changes in both Arg-320 and Arg-271 cleavage rates result together in a moderate change in the pathway of prothrombin activation. Although residues 499-505 directly precede the Arg-506 cleavage site for activated protein C (APC), the 499-505(VIII) FVa mutant was inactivated entirely normally by APC. These results suggest that this A2 domain sequence of the FVa and FVIIIa cofactors evolved to have different specificity for binding FXa and FIXa while retaining compatibility as substrate for APC. In an updated three-dimensional model for the FVa structure, residues 499-505, along with Arg-506, Arg-306, and other previously suggested FXa binding sequences, delineate a continuous surface on the A2 domain that is strongly implicated as an extended FXa binding surface in the prothrombinase complex. 相似文献
77.
Radhika V Proikas-Cezanne T Jayaraman M Onesime D Ha JH Dhanasekaran DN 《Nature chemical biology》2007,3(6):325-330
With the increasing threat of environmental toxicants including biological and chemical warfare agents, fabricating innovative biomimetic systems to detect these harmful agents is critically important. With the broad objective of developing such a biosensor, here we report the construction of a Saccharomyces cerevisiae strain containing the primary components of the mammalian olfactory signaling pathway. In this engineered yeast strain, WIF-1alpha, olfactory receptor signaling is coupled to green fluorescent protein expression. Using this 'olfactory yeast', we screened for olfactory receptors that could report the presence of the odorant 2,4-dinitrotoluene, an explosive residue mimic. With this approach, we have identified the novel rat olfactory receptor Olfr226, which is closely related to the mouse olfactory receptors Olfr2 and MOR226-1, as a 2,4-dinitrotoluene-responsive receptor. 相似文献
78.
Juana Martinez Kritika Subramanian Daniel Margolis Elisabeth O'Dwyer Joseph Osborne Yuliya Jhanwar Himanshu Nagar Nicholas Williams Arindam RoyChoudhury Gabriela Madera John Babich Sandra Huicochea Castellanos 《Translational oncology》2022,15(1)
BackgroundThe primary objective was to compare the overall diagnostic performance, presented as detection rate of 68Ga-PSMA-HBED-CC positron emission tomography/magnetic resonance imaging (PSMA PET/MRI) versus conventional, multiparametric MRI (mpMRI) in a population of patients with biochemically recurrent prostate cancer. In conjunction with this analysis, secondary objectives included the evaluation of the detection rate stratified by PSA levels and primary treatment modality.MethodsA total of 165 PSMA PET MRI were performed from April 2018 to May 2021, of whom 108 were presenting for biochemical recurrent disease. The PSMA PET vertex to thigh were read by two different board-certified nuclear medicine physicians while the MRI head and neck, chest, abdomen, and pelvis (with dedicated, PI-RADS compliant multiparametric prostate MRI) were read by two board certified diagnostic radiologists.AnalysisPSMA PET/MRI had a higher detection rate than mpMRI when evaluating patients with biochemical recurrence (BCR) with similar results demonstrated when sub-analysis was performed using PSA levels, primary treatment modality, and time since androgen deprivation therapy. Our study also showed PSMA PET/MRI had a higher sensitivity than mpMRI.DiscussionOur findings demonstrate that PSMA PET/MRI is a better imaging modality in the detection of disease in the setting of BCR when compared to MRI alone. Combined utility with PSMA PET/MRI is a powerful tool which can aid in not only the detection of disease, but also guide in treatment planning for prostate cancer patients. 相似文献
79.
Andrew E Rosselot Miri Park Mari Kim Toru MatsuUra Gang Wu Danilo E Flores Krithika R Subramanian Suengwon Lee Nambirajan Sundaram Taylor R Broda Heather A McCauley Jennifer A Hawkins Kashish Chetal Nathan Salomonis Noah F Shroyer Michael A Helmrath James M Wells John B Hogenesch Sean R Moore Christian I Hong 《The EMBO journal》2022,41(2)
80.
Mythreyi Narasimhan Vaishnavi Khamkar Sarika Tilwani Sorab N. Dalal Dhanlaxmi Shetty P.G. Subramanian Sanjay Gupta Rukmini Govekar 《Journal of cell communication and signaling》2022,16(2):207
Chronic myeloid leukemia (CML) epitomises successful targeted therapy, where inhibition of tyrosine kinase activity of oncoprotein Bcr-Abl1 by imatinib, induces remission in 86% patients in initial chronic phase (CP). However, in acute phase of blast crisis, 80% patients show resistance, 40% among them despite inhibition of Bcr-Abl1 activity. This implies activation of either Bcr-Abl1- independent signalling pathways or restoration of signalling downstream of inactive Bcr-Abl1. In the present study, mass spectrometry and subsequent in silico pathway analysis of differentiators in resistant CML-CP cells identified key differentiators, 14–3-3ε and p38 MAPK, which belong to Bcr-Abl1 pathway. Their levels and activity respectively, indicated active Bcr-Abl1 pathway in CML-BC resistant cells, though Bcr-Abl1 is inhibited by imatinib. Further, contribution of these components to resistance was demonstrated by inhibition of Bcr-Abl1 down-stream signalling by knocking-out of 14–3-3ε and inhibition of p38 MAPK activity. The observations merit clinical validation to explore their translational potential.Supplementary InformationThe online version contains supplementary material available at 10.1007/s12079-021-00647-x. 相似文献