Publications by authors named "Ruzica Bago"

Article Synopsis
  • The study focuses on how the mTORC1 pathway plays a crucial role in cancer cell growth by regulating polyamine dynamics, which are vital for tumor development.
  • Researchers used metabolomics on mouse models and human prostate cancer biopsies, discovering that mTORC1 alters the production of key metabolites like dcSAM and affects the stability of the enzyme AMD1.
  • Findings show that high AMD1 levels correlate with active mTORC1 in human prostate cancer, while patients treated with the mTORC1 inhibitor everolimus experienced reduced AMD1 levels and cell proliferation, highlighting mTORC1's role in oncogenic metabolism.
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Human papillomaviruses enter host cells via a clathrin-independent endocytic pathway involving tetraspanin proteins. However, post-endocytic trafficking required for virus capsid disassembly remains unclear. Here we demonstrate that the early trafficking pathway of internalised HPV particles involves tetraspanin CD63, syntenin-1 and ESCRT-associated adaptor protein ALIX.

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We explore mechanisms that enable cancer cells to tolerate PI3K or Akt inhibitors. Prolonged treatment of breast cancer cells with PI3K or Akt inhibitors leads to increased expression and activation of a kinase termed SGK3 that is related to Akt. Under these conditions, SGK3 is controlled by hVps34 that generates PtdIns(3)P, which binds to the PX domain of SGK3 promoting phosphorylation and activation by its upstream PDK1 activator.

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PIK3CA, which encodes the p110α subunit of PI3K, is frequently mutated and oncogenic in breast cancer. PI3Kα inhibitors are in clinical development and despite promising early clinical activity, intrinsic resistance is frequent among patients. We have previously reported that residual downstream mTORC1 activity upon treatment with PI3Kα inhibitors drives resistance to these agents.

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The Vps34 (vacuolar protein sorting 34) class III PI3K (phosphoinositide 3-kinase) phosphorylates PtdIns (phosphatidylinositol) at endosomal membranes to generate PtdIns(3)P that regulates membrane trafficking processes via its ability to recruit a subset of proteins possessing PtdIns(3)P-binding PX (phox homology) and FYVE domains. In the present study, we describe a highly selective and potent inhibitor of Vps34, termed VPS34-IN1, that inhibits Vps34 with 25 nM IC50 in vitro, but does not significantly inhibit the activity of 340 protein kinases or 25 lipid kinases tested that include all isoforms of class I as well as class II PI3Ks. Administration of VPS34-IN1 to cells induces a rapid dose-dependent dispersal of a specific PtdIns(3)P-binding probe from endosome membranes, within 1 min, without affecting the ability of class I PI3K to regulate Akt.

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Nucleoside diphosphate kinases (NDPKs) are ubiquitous phosphotransfer enzymes responsible for producing most of the nucleoside triphosphates except for ATP. This role is important for the synthesis of nucleic acids and proteins and the metabolism of sugars and lipids. Apart from this housekeeping role NDPKs have been shown to have many regulatory functions in diverse cellular processes including proliferation and endocytosis.

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Syntenin-1 is a PDZ domain-containing adaptor that controls trafficking of transmembrane proteins including those associated with tetraspanin-enriched microdomains. We describe the interaction of syntenin-1 with ubiquitin through a novel binding site spanning the C terminus of ubiquitin, centered on Arg(72), Leu(73), and Arg(74). A conserved LYPSL sequence in the N terminus, as well as the C-terminal region of syntenin-1, are essential for binding to ubiquitin.

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Background: Nucleoside diphosphate kinases NDPK are evolutionarily conserved enzymes present in Bacteria, Archaea and Eukarya, with human Nme1 the most studied representative of the family and the first identified metastasis suppressor. Sponges (Porifera) are simple metazoans without tissues, closest to the common ancestor of all animals. They changed little during evolution and probably provide the best insight into the metazoan ancestor's genomic features.

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Many of the expanding roles of nucleoside diphosphate kinase have been attributed to its ability to interact with other proteins. One proposal is an interaction with the cellular energy sensor AMP-activated protein kinase, and here, we apply the simple eukaryotic organism, Dictyostelium discoideum as a test model. Stable cotransformants were created in which NDPK expression was knocked down by antisense inhibition, and AMPK activity was chronically elevated either by constitutive overexpression of its active, catalytic domain (AMPKαT) or as a result of mitochondrial dysfunction (created by antisense inhibition of expression of a mitochondrial chaperone protein, chaperonin 60).

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The family of Nm23/NDPK (nucleoside diphosphate kinase) proteins regulates a vast variety of cellular processes and, therefore, participates in important physiological events like proliferation, differentiation, molecular transport, and apoptosis. The majority of experimental data concerning this gene family has been focused on their engagement in metastasis formation--a critical point in tumor progression. In spite of the growing amount of evidence suggesting the multifunctional role of nm23/NDPKs the specific functions of every particular family member is still elusive.

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Article Synopsis
  • Nm23-H1 is identified as a metastatic suppressor gene that reduces the metastatic potential in carcinoma cell lines but its exact mechanism of action remains unclear.
  • Research focused on CAL 27 cells (oral squamous cell carcinoma) showed that those overexpressing nm23-H1 had lower migratory and invasive abilities and exhibited stronger adhesion on certain substrates.
  • Findings indicate that nm23-H1 enhances cell adhesion without disrupting EGF-induced Ras signaling, providing insights into its role in regulating cell behavior in cancer.
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The human nm23-H1 was discovered as a tumor metastasis suppressor based on its reduced expression in melanoma cell lines with low versus high metastatic potential. It encodes for one of two subunits of the nucleoside-diphosphate kinase. Besides its role in the maintenance of the cells NTP pool, nm23 plays a key role in different cellular processes.

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The human Nm23-H1/NDPK A and Nm23-H2/NDPK B encode for two subunits of nucleoside diphosphate kinase--a ubiquitous enzyme that transfers the terminal phosphates from ATP to (d)NDPs. Although having an 88% amino acid sequence identity and an already assigned biochemical role in the cell, the two subunits appear to have additional and distinctive cell functions. In particular, both subunits have been reported to be involved in tumor progression and metastasis.

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Combined cytogenetic, fluorescence in situ hybridization (FISH), and molecular analysis are useful in the diagnosis of sex chromosome aberrations. These methods were used in karyotype analysis of a 4-year-old girl with mild dysmorphism and growth retardation. Standard cytogenetic and FISH analysis was done on slides obtained from peripheral blood lymphocyte culture, and the molecular study was performed by using DNA polymorphism analysis.

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We present a case of trisomy for the whole short arm of chromosome 6 in a 3-year-old girl with moderate mental retardation, mild facial dysmorphism, short stature, failure to thrive, and no abnormalities of the visceral organs. Cytogenetic and fluorescence in situ hybridization (FISH) analysis revealed a 46, X, der(X)t(X;6)(q22; p11.1) karyotype.

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