Cells respond to the shift of intracellular environment toward pro-oxidant conditions by activating the transcription of numerous "antioxidant" genes. This response is based on the activation of the Nrf2 transcription factor, which transactivates the genes containing in their promoters the antioxidant response cis-elements (AREs). If the oxidative stress provokes DNA damage, a second response of the cell takes place, based on the activation of p53, which induces cell cycle arrest and/or apoptosis. Here we have explored the cross-talk between these two regulatory mechanisms. The results show that p53 counteracts the Nrf2-induced transcription of three ARE-containing promoters of the x-CT, NQO1, and GST-␣1 genes. Endogenous transcripts of these antioxidant genes accumulate as a consequence of Nrf2 overexpression or exposure to electrophile diethylmaleate, but these effects are again blocked by p53 overexpression or endogenous p53 activation. Chromatin immunoprecipitation experiments support the hypothesis that this p53-dependent trans-repression is due to the direct interaction of p53 with the ARE-containing promoters. Considering that p53-induced apoptosis requires an accumulation of reactive oxygen species, this negative control on the Nrf2 transactivation appears to be aimed to prevent the generation of a strong antioxidant intracellular environment that could hinder the induction of apoptosis.
Prolonged infection of uterine cervix epithelium with human papillomavirus (HPV) and constitutive expression of viral oncogenes have been recognized as the main cause of the complex molecular changes leading to transformation of cervical epithelial cells. Deregulated expression of microRNAs (miRNA), long non-coding RNAs (lncRNA), and circular RNAs (circRNA) is involved in the initiation and promotion processes of cervical cancer development. Expression profiling of small RNAs in cervical neoplasia revealed up-regulated "oncogenic" miRNAs, such as miR-10a, miR-21, miR-19, and miR-146a, and down regulated "tumor suppressive" miRNAs, including miR-29a, miR-372, miR-214, and miR-218, associated with cell growth, malignant transformation, cell migration, and invasion. Also several lncRNAs, comprising among others HOTAIR, MALAT1, GAS5, and MEG3, have shown to be associated with various pathogenic processes such as tumor progression, invasion as well as therapeutic resistance and emerged as new diagnostic and prognostic biomarkers in cervical cancer. Moreover, human genes encoded circular RNAs, such as has_circ-0018289, have shown to sponge specific miRNAs and to concur to the deregulation of target genes. Viral encoded circE7 has also demonstrated to overexpress E7 oncoprotein thus contributing to cell transformation. In this review, we summarize current literature on the complex interplay between miRNAs, lncRNAs, and circRNAs and their role in cervical neoplasia.
The -amyloid precursor protein (APP) 1 is an integral membrane protein from which the -amyloid peptide is generated. The -amyloid peptide forms the extracellular insoluble aggregates characteristic of Alzheimer's disease. The function of APP and the regulation of the proteolytic events generating the -amyloid peptide are still unknown. APP was expected to be involved in signal transduction processes, because of its transmembrane topology. Three main isoforms of APP exist, generated by alternative splicing (APP 770 , APP 751 , and APP 695 ) and all possessing the same intracellular domain (reviewed in Ref.1). Although little is known about the putative extracellular ligand(s) for APP, several results describe the interaction of its intracellular domain with other proteins. These include the interaction with the heterotrimeric G protein Go (2), a 59-kDa ubiquitously expressed protein named APP-BP1 (3), the X11 protein (4), the neuron-abundant Fe65 protein, and an Fe65-like protein (4 -6). It was shown that intact APP binds to oligomeric Go protein and that the intracellular region of APP spanning residues 657-676 activates Go (2, 7). Furthermore, the interaction of APP with a monoclonal antibody directed against its extracellular domain mimics a ligand-receptor binding that triggers Go activation (7). APP-BP1 interacts both in vitro and in vivo with the carboxyl-terminal region of APP, which represents its intracellular domain. This protein is homologous to the product of the Arabidopsis auxin resistance gene AXR1 and to a Caenorabditis elegans protein of unknown function (3).The Fe65 gene is mainly expressed in the neurons of specific regions of the mammalian nervous system (8, 9) and encodes a protein containing two different types of protein-protein interaction domains: the WW domain (reviewed in Ref. 10) and the phosphotyrosine interaction/phosphotyrosine binding (PID/ PTB) domain (reviewed in Ref. 11). The latter was found in the oncoprotein Shc (12, 13), in its relatives , in other apparently unrelated proteins, such as Numb, X11, and Dab (15), and in insulin receptor substrate 1 (IRS-1) and 17). The PID/PTB domains interact with phosphotyrosine residues located in the intracellular domains of growth factor receptors, such as EGF-R, trkA, and plateletderived growth factor receptor in the case of Shc (13) and insulin receptor and interleukin 4 receptor in the case of IRS-1 (16). In contrast, the Fe65 region containing the two PID/PTB domains was demonstrated to interact with the intracellular domain of APP (5).All the PID/PTB domains present in the Shc family, IRS-1, and Fe65 interact with intracellular regions of membrane proteins containing the consensus motif ⌽XNPXY (where ⌽ is hydrophobic and X is any amino acid). However, Fe65 possesses at least two unique characteristics: (i) although all the known members of the PID/PTB family contain only one PID/ PTB element (13), Fe65 is an exception, because its sequence interacting with APP shows two consecutive PID/PTB domains; and (ii) although the Tyr prese...
Here we show that replicative senescence in normal human diploid IMR90 fibroblasts is accompanied by altered expression of a set of microRNAs (miRNAs) (senescence-associated miRNAs), with 14 and 10 miRNAs being either up or downregulated (42-fold), respectively, in senescent with respect to young cells. The expression of most of these miRNAs was also deregulated upon senescence induced by DNA damage (etoposide) or mild oxidative stress (diethylmaleate). Four downregulated miRNAs were part of miRNA family-17, recently associated to human cell and tissue aging. Moreover, eight upregulated and six downregulated miRNAs mapped in specific chromosomal clusters, suggesting common transcriptional regulation. Upon adoptive overexpression, seven upregulated miRNAs induced the formation of senescence-associated heterochromatin foci and senescence-associated b-galactosidase staining (Po0.05), which was accompanied, in the case of five of them, by reduced cell proliferation. Finally, miR-210, miR-376a*, miR-486-5p, miR-494, and miR-542-5p induced double-strand DNA breaks and reactive oxygen species accumulation in transfected cells. In conclusion, we have identified a set of human miRNAs induced during replicative and chemically induced senescence that are able to foster the senescent phenotype by prompting DNA damage. Replicative or cellular senescence, a state of irreversible arrest of cell division, was first described in cultures of human fibroblasts. 1 Since then, replicative senescence has been described in various mammalian cells. 2 The mechanisms underlying senescence include telomere shortening, upregulation of the CDKN1A (p21WAF1) and CDKN2A (p16INK4a and p14ARF) loci, and accumulation of DNA damage. 3 Telomeres become progressively shorter at every round of cell division and this leads to critically short telomere length sensed as double-strand DNA breaks. 4 DNA damage and DNA-damage response (DDR) could be common events to cellular senescence programs initiated by telomere dysfunction and aberrant oncogene activation. 5 Senescent cells are marked by lack of DNA replication; expression of senescence-associated b-galactosidase (SA-b-gal); accumulation of discrete nuclear foci that are termed senescence-associated heterochromatin foci (SAHFs); and senescence-associated DNA-damage foci (SDFs). SAHFs are detected by preferential binding of DNA dyes, such as 4 0 ,6-diamidino-2-phenylindole (DAPI), and the presence of certain heterochromatin-associated histone modifications (trimethyl-Lys9 Histone H3). SDFs are nuclear foci containing proteins that are associated to DNA damage (Ser139-phosphorylated histone H2AX -g-H2AX-and p53-binding protein-1-53BP1). 6 Senescent cells show striking changes in gene expression, including upregulation of cell-cycle inhibitors (p21WAF1 and p16INK4a) and secreted proteins involved in microenvironment remodeling (IL-6), 7 and downregulation of genes that facilitate cell-cycle progression (c-FOS, cyclin-A, cyclin-B, PCNA) 8 or that are involved in cell-cycle execution (FOXM1, UBE2C, TYMS). ...
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