Search results for "Suppressor"
showing 10 items of 532 documents
The Stress-Inducible Protein DRR1 Exerts Distinct Effects on Actin Dynamics.
2018
Cytoskeletal dynamics are pivotal to memory, learning, and stress physiology, and thus psychiatric diseases. Downregulated in renal cell carcinoma 1 (DRR1) protein was characterized as the link between stress, actin dynamics, neuronal function, and cognition. To elucidate the underlying molecular mechanisms, we undertook a domain analysis of DRR1 and probed the effects on actin binding, polymerization, and bundling, as well as on actin-dependent cellular processes. Methods: DRR1 domains were cloned and expressed as recombinant proteins to perform in vitro analysis of actin dynamics (binding, bundling, polymerization, and nucleation). Cellular actin-dependent processes were analyzed in trans…
Telomeres and Telomerase During Human Papillomavirus-Induced Carcinogenesis
2018
Human papillomaviruses (HPVs) belong to a small spherical virus family and are transmitted through direct contact, most often through sexual behavior. More than 200 types of HPV are known, a dozen or so of which are classified as high-risk viruses (HR HPV) and may contribute to the development of cervical cancer. HPV is a small virus with a capsid composed of L1 and L2 proteins, which are crucial for entry to the cell. The infection begins at the basal cell layer and progresses to involve cells from higher layers of the cervical epithelium. E6 and E7 viral proteins are involved in the process of carcinogenesis. They interact with suppressors of oncogenesis, including p53 and Rb proteins. Th…
Acute depletion of telomerase components DKC1 and NOP10 induces oxidative stress and disrupts ribosomal biogenesis via NPM1 and activation of the P53…
2020
Mutations in DKC1, NOP10, and TINF2 genes, coding for proteins in telomerase and shelterin complexes, are responsible for diverse diseases known as telomeropathies and ribosomopathies, including dyskeratosis congenita (DC, ORPHA 1775). These genes contribute to the DC phenotype through mechanisms that are not completely understood. We previously demonstrated in models of DC that oxidative stress is an early and independent event that occurs prior to telomere shortening. To clarify the mechanisms that induce oxidative stress, we silenced genes DKC1, NOP10, and TINF2 with siRNA technology. With RNA array hybridisation, we found several altered pathways for each siRNA model. Afterwards, we ide…
11q Deletion or ALK Activity Curbs DLG2 Expression to Maintain an Undifferentiated State in Neuroblastoma
2020
High-risk 11q deleted neuroblastomas typically display undifferentiated/poorly differentiated morphology. Neuroblastoma is thought to develop from Schwann cell precursors and undifferentiated neural crest (NC) derived cells. It is therefore vital to understand mechanisms involved in the block of differentiation. We identify an important role for oncogenic ALK-ERK1/2-SP1 signaling in maintenance of undifferentiated NC-derived progenitors via repression of DLG2, a tumor suppressor in neuroblastoma. DLG2 is expressed in the ‘bridge signature’ that represents the transcriptional transition state when neural crest cells or Schwann Cell Precursors become chromaffin cells of the adrenal gland. We …
E4BP4/NFIL3 modulates the epigenetically repressed RAS effector RASSF8 function through histone methyltransferases
2018
RAS proteins are major human oncogenes, and most of the studies are focused on enzymatic RAS effectors. Recently, nonenzymatic RAS effectors (RASSF, RAS association domain family) have garnered special attention because of their tumor-suppressive properties in contrast to the oncogenic potential of the classical enzymatic RAS effectors. Whereas most members of RASSF family are deregulated by promoter hypermethylation, RASSF8 promoter remains unmethylated in many cancers but the mechanism(s) of its down-regulation remains unknown. Here, we unveil E4BP4 as a critical transcriptional modulator repressing RASSF8 expression through histone methyltransferases, G9a and SUV39H1. In line with these …
MiR-663, a MicroRNA Linked with Inflammation and Cancer That Is under the Influence of Resveratrol
2018
Resveratrol (trans-3,5,4′-trihydroxystilbene, RSV) is a non-flavonoid dietary polyphenol with antioxidant, anti-inflammatory and anti-cancer properties that is primarily found in red berries. While RSV displays many beneficial effects in vitro, its actual effects in vivo or in animal models remain passionately debated. Recent publications suggest that RSV pleiotropic effects could arise from its capability to regulate the expression and activity of microRNAs, short regulators themselves capable of regulating up to several hundreds of target genes. In particular, RSV increases microRNA miR-663 expression in different human cell lines, suggesting that at least some of its multiple benef…
P14ARF: The Absence that Makes the Difference
2020
P14ARF is a tumor suppressor encoded by the CDKN2a locus that is frequently inactivated in human tumors. P14ARF protein quenches oncogene stimuli by inhibiting cell cycle progression and inducing apoptosis. P14ARF functions can be played through interactions with several proteins. However, the majority of its activities are notoriously mediated by the p53 protein. Interestingly, recent studies suggest a new role of p14ARF in the maintenance of chromosome stability. Here, we deepened this new facet of p14ARF which we believe is relevant to its tumor suppressive role in the cell. To this aim, we generated a monoclonal HCT116 cell line expressing the p14ARF cDNA cloned in the piggyback vector …
Myeloid-Derived Suppressor Cells Specifically Suppress IFN-γ Production and Antitumor Cytotoxic Activity of Vδ2 T Cells.
2018
γδ T cells represent less than 5% of circulating T cells; they exert a potent cytotoxic function against tumor or infected cells and secrete cytokines like conventional αβ T cells. As αβ T cells γδ T cells reside in the typical T cell compartments (the lymph nodes and spleen), but are more widely distributed in tissues throughout the body. For these reasons, some investigators are exploring the possibility of immunotherapies aimed to expand and activate Vδ2 T cells, or using them as Chimeric Antigen Receptor carriers. However, the role of immunosuppressive microenvironment on Vδ2 T cells during infections and cancers has not been completely elucidated. In particular, the effects of myeloid-…
Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells
2021
The carbazole compounds PK9320 (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and PK9323 (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of PK083 (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily pr…
Structural Basis of the High Affinity Interaction between the Alphavirus Nonstructural Protein-3 (nsP3) and the SH3 Domain of Amphiphysin-2
2016
We show that a peptide from Chikungunya virus nsP3 protein spanning residues 1728–1744 binds the amphiphysin-2 (BIN1) Src homology-3 (SH3) domain with an unusually high affinity (Kd 24 nM). Our NMR solution complex structure together with isothermal titration calorimetry data on several related viral and cellular peptide ligands reveal that this exceptional affinity originates from interactions between multiple basic residues in the target peptide and the extensive negatively charged binding surface of amphiphysin-2 SH3. Remarkably, these arginines show no fixed conformation in the complex structure, indicating that a transient or fluctuating polyelectrostatic interaction accounts for this …