1,721,093 research outputs found
Initiation of mRNA Translation in Oncogenesis: The Role of eIF4E
No full textThe eukaryotic initiation factor 4E (eIF4E) is a key regulator of protein translation whose function is activated by the Akt and Ras proto-oncogenic signal transduction pathways. eIF4E enhances the translation of mRNAs encoding several genes involved in tumorigenesis and acts as a proto-oncogene, in vitro, when overexpressed in immortalized cells. Importantly, eIF4E is frequently found overexpressed in human cancers of multiple histological origins. However, in vivo evidence of the eIF4E neoplastic potential was lacking until now. Here we discuss recent findings that demonstrate eIF4E's oncogenic role in vivo through direct genetic approaches in the mouse, and identify novel oncogenic functions for this initiation factor in cooperative tumorigenesis and response to therapy
The promyelocytic leukaemia protein tumour suppressor functions as a transcriptional regulator of p63
No full textMitochondria associated membranes (MAMs) as critical hubs for apoptosis
No full textApoptosis is a process of major biomedical interest, since its deregulation is involved in the pathogenesis of a broad variety of disorders (neoplasia, autoimmune disorders, viral and neurodegenerative diseases, to name a few). It is now firmly established that variations in cellular calcium (Ca2+) concentration are pivotal in the control of a variety of cellular functions. Strong evidence has been accumulated supporting a central role of Ca2+ in the regulation of cell death.
In particular, in the context of the biochemical mechanisms of apoptosis, increasing evidence support a role for endoplasmic reticulum (ER)-mitochondria Ca2+ cross talk as a crucial regulator of several pathways of apoptosis. Recent data highlight as also the promyelocytic leukemia protein (PML), by modulating the ER machinery at the contact sites between ER and mitochondria (the mitochondria associated membranes, MAMs), regulates cell survival through the ER-cytosol/mitochondria Ca2+ signaling
Disruption of PLZP in mice leads to increased T-lymphocytes proliferation, cytokine production and altered hematopoietic stem cell homeostasis
No full textDeregulated function of members of the POK (POZ and Kruppel) family of transcriptional repressors, such as promyelocytic leukemia zinc finger (PLZF) and B-cell lymphoma 6 (BCL-6), plays a critical role in the pathogenesis of acute promyelocytic leukemia (APL) and non-Hodgkin's lymphoma, respectively. PLZP, also known as TZFP, FAZF, or ROG, is a novel POK protein that displays strong homology with PLZF and has been implicated in the pathogenesis of the cancer-predisposing syndrome, Fanconi's anemia, and of APL, in view of its ability to heterodimerize with the FANC-C and PLZF proteins, respectively. Here we report the generation and characterization of mice in which we have specifically inactivated the PLZP gene through in-frame insertion of a lacZ reporter and without perturbing the expression of the neighboring MLL2 gene. We show that PLZP-deficient mice display defects in cell cycle control and cytokine production in the T-cell compartment. Importantly, PLZP inactivation perturbs the homeostasis of the hematopoietic stem and/or progenitor cell. On the basis of our data, a deregulation of PLZP function in Fanconi's anemia and APL may affect the biology of the hematopoietic stem cell, in turn contributing to the pathogenesis of these disorders
Growth and tumor suppressive properties of the PML gene of acute promyelocytic leukemia in PML-/- mice
No full textCD8 T cell-intrinsic GITR is required for T cell clonal expansion and mouse survival following severe influenza infection.
No full textThe regulation of T cell expansion by TNFR family members plays an important role in determining the magnitude of the immune response to pathogens. As several members of the TNFR family, including glucocorticoid-induced TNFR-related protein (GITR), are found on both regulatory and effector T cells, there is much interest in understanding how their effects on these opposing arms of the immune system affect disease outcome. Whereas much work has focused on the role of GITR on regulatory T cells, little is known about its intrinsic role on effector T cells in an infectious disease context. In this study, we demonstrate that GITR signaling on CD8 T cells leads to TNFR-associated factor (TRAF) 2/5-dependent, TRAF1-independent NF-kappa B induction, resulting in increased Bcl-x(L). In vivo, GITR on CD8 T cells has a profound effect on CD8 T cell expansion, via effects on T cell survival. Moreover, GITR is required on CD8 T cells for enhancement of influenza-specific CD8 T cell expansion upon administration of agonistic anti-GITR Ab, DTA-1. Remarkably, CD8 T cell-intrinsic GITR is essential for mouse survival during severe, but dispensable during mild respiratory influenza infection. These studies highlight the importance of GITR as a CD8 T cell costimulator during acute viral infection, and argue that despite the similarity among several TNFR family members in inducing T lymphoctye survival, they clearly have nonredundant functions in protection from severe infectio
Preferential expression of the transcription coactivator HTIF1alpha gene in acute myeloid leukemia and MDS-related AML
No full textHTIF1α, a transcription coactivator which is able to mediate RARα activity and functionally interact with PML, is encoded by a gene on chromosome 7q32–34, which is a critical region in acute myeloid leukemias (AML). With the assumption that this gene may be related to AML, we investigated the HTIF1α DNA structure and RNA expression in leukemic cells from 36 M1–M5 AML patients (28 ‘de novo’ and eight ‘secondary’ to myelodysplastic syndrome (MDS)). Abnormal HTIF1α DNA fragments were never found, whereas loss of HTIF1α DNA was observed in the patients with chromosome 7q32 deletion and translocation, and in one case without detectable chromosome 7 abnormality. HTIF1α RNA was found in acute myelocytic leukemic blasts, and was almost undetectable in normal mononuclear cells. The expression varied among the patients: higher in M1 to M3 subtypes, with the highest values in M1; low levels were constantly observed in M4 and M5 AML. In addition, HTIF1α was significantly overexpressed in MDS-related AML (MDR-AML), but not in MDS. We also found that HTIF1α expression was high in myeloid cell lines. In myeloblastic HL60 and promyelocytic NB4 cells, induced to differentiate along the monocytic–macrophage pathway by TPA or vitamin D3, HTIF1α expression decreased, whereas it was maintained at high levels on induction to granulocytic differentiation by RA or DMSO. In K562 cells, HTIF1α RNA levels did not change after hemin-induced erythroid differentiation. These results suggest that HTIF1α could play a role in myeloid differentiation, being distinctly regulated in hematopoietic lineages
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
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