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Mutations of the four leucine residues within the Rex-activation domain demonstrate that they are critical for nuclear export of mRNA and this interaction requires a hydrophobic region 32 , Rex was also shown to bind to the CRM1 receptor in cooperation with RanGTP and RanBP3, a scaffold protein that aids in the formation of the protein-export complex, in addition to binding to RCC1 to promote more efficient Ran nucleotide exchange 38 , Control of viral mRNA trafficking by Rex and p Furthermore, mutations of Rex and Rev that failed to form multimers act as dominant-negative mutants, suggesting that multimerization is critical for the functions of these proteins Although multimerization was found to be critical for Rex function, Rex Mutants defective for multimerization retained their ability to shuttle in and out of the nucleus The importance of Rex multimerization was highlighted using an in vivo rat model.
In these models, the activity of Rex has been found to be quite low compared to that in human cells and this failure was due to the rat CRM1. These two domains along with residues and overlap with the region required for efficient binding of CRM1 to the scaffold protein RanBP3, suggesting that the multimerization of Rex and the interaction with RanBP3-CRM1 are linked An increased number of Rex proteins would also facilitate binding of a larger number of CRM1 proteins, allowing for more efficient nuclear export.
Studies have also shown that translation-initiation factor eIF-5A may play a part in the formation of the Rex homo-oligomers Rex function requires this large stem-loop and a nucleotide subregion within the RXRE of viral transcripts, which directly interacts with the Rex protein 50 — Rex shares many features with its homolog HIV Rev.
While Rex and Rev have very little sequence homology, they both are functionally and structurally similar. In fact, Rex and Rev both have an arginine-rich region that is responsible for binding to their respective response elements; however, only Rex can functionally substitute for Rev 51 , 53 — 55 using a Rev-deficient HIV-1 provirus The minimum continuous regions within the RRE that are required for Rex and Rev functions differ between the two proteins, with Rex requiring a longer region of the RRE to bind nt to nt While the reason for this remains unclear, one possible explanation is that Rex binding to the RXRE stabilizes a complex secondary structure that bridges the poly-A signal and the poly-A site together since these are unusually far apart in the HTLV-1 genome Fig.
The structure of the stem-loop allows the AAUAAA hexamer and GU-rich elements to come into close contact, which then serves as a signal for polyadenylation. Mutations of the arginine residues contained in this domain prevent Rex from nuclear accumulation and from binding to RXRE sequences Interestingly, the arginine-rich region has recently been found to be involved in Rex-p30 interactions Rex and p30 functional domains and structures.
Rex activities have been shown to be regulated by phosphorylation since treatment of an HTLV-1 infected cell line with a protein kinase inhibitor blocked the cytoplasmic accumulation of unspliced gag-pol mRNA Phosphorylation of serine 70 in Rex appeared to be dependent on cellular protein kinase C Rex was also found to be phosphorylated on serine and threonine The exact role of Rex phosphorylation still remains to be determined.
Rex has also been shown to increase FynB p59fyn expression, possibly by affecting FynB splicing FynB is a src family protein-tyrosine kinase that regulates T-cell receptor stimulation Co-transfection experiments in Jurkat T-cells demonstrated that Rex could augment Tax in increasing vascular cell adhesion molecule-1 VCAM-1 and lymphocyte function-associated antigen-3 LFA-3 expression Although considerable knowledge about the role of Rex in virus replication has been gained, important questions still remain as to how Rex is able to regulate some viral mRNA but not others since all HTLV-1 transcripts contain an RXRE sequence.
If both Tax and Rex act as positive regulators of viral gene expression, how is the virus able to reduce its expression and evade immune defenses?
Answers to these questions came in when a negative viral posttranscriptional regulator was described. In the last decade several investigators have started to uncover the functions of additional HTLV-1 accessory proteins encoded by the pX region p12, p13, and p30 73 — Although it has been proposed that most of these proteins are dispensable for in vitro human T-cell immortalization 67 , 76 , 77 , in our experience such cell lines have multiple growth defects in vitro.
Nonetheless, several aspects about these small regulatory proteins are irrefutable. They are also expressed in vivo since both cell-mediated and antibody immune responses directed against these proteins have been detected in infected patients 81 , These regulatory proteins play critical roles for in vivo infectivity in a rabbit model 83 — These genes may have already accomplished their functions prior to being mutated.
In fact, isolates with a stop codon in the tax open reading frame have been reported. Recent reviews have described in detail the functions of the p12 and p13 proteins 73 , The p30 protein is intriguing because it is reported to act as both a transcriptional and posttranscriptional regulator, a characteristic shared by another nucleolar resident protein, nucleolin.
The p30 has similarities with serine-rich proteins, including several transcriptional activators such as oct-1, oct-2, pit-1, engrailed, and POU-Mi transcription factors Transient transfection experiments confirmed the transcriptional activity of p30 in Gal4 experiments. In addition, DNA microarray studies also showed that p30 was able to modify the expression profile of key cellular genes involved in leukemogenesis The transcriptional activities of p30 have been reviewed 73 , This review focuses on the posttranscriptional activity of p30 and the interplay with Rex.
Similar results were subsequently obtained using p28, a p30 homolog, in HTLV-2 This is a unique example of negative regulation among viruses. The p30 contains a sequence with homology to a NES, but heterokaryon assays demonstrated that, unlike Rex, p30 is a non-shuttling protein In addition, p30 does not interact with CRM1 and a mutation, which restores the consensus NES sequence Ser to Leu , does not provide shuttling capability to p30 unpublished data.
The nucleolus is not membrane bound and its structure is maintained by an accumulation of ribosomal RNA and proteins such as nucleolin or protein B Most proteins are only transiently retained in the nucleolus through protein or RNA interactions, and proteins with longer resident times usually harbor specific signals These signals tend to be nucleolar retention signals, generally characterized by sequences rich in arginine and lysine 91 , In vivo kinetics of p30 fused to a green fluorescent protein GFP-p30 in the nuclear and nucleolar compartments, analyzed by live cell imaging, indicated that p30 is highly mobile in the nucleus but very static in the nucleolus In cells expressing GFP-p30, only a small fraction of the fluorescence signal was lost within the first five seconds after a bleaching event, followed by a slower decline of the nucleolar signal.
Surprisingly, the kinetics of GFP-p30 are very similar to nucleolar methyltransferase fibrillarin-GFP, suggesting that p30 is tightly bound to nucleolar components Single substitution of any Arg had no effect on nucleolar localization. In the same study, localization of various truncated forms of p30 revealed the presence of four NLS domains in p30 Fig.
Many viruses encode for nucleolar proteins, which are involved in the replication of viral genomes, as well as in the transcriptional and posttranscriptional regulation of gene expression 95 , The use of mutants of p30 unable to accumulate into the nucleolus indicated that nucleolar localization of p30 is dispensable for its transcriptional and posttranscriptional effects Nucleoli are mainly the sites of ribosome biogenesis, a highly complex process leading to the production of pre-ribosomal particles, which are then released into the nucleoplasm and exported to the cytoplasm as mature ribosomal subunits.
Confocal microscopy indicated that a GFP-p30 fusion protein localized to the granular center 93 , which is the site of pre-ribosome assembly. Interestingly, p30 was also found to interact with L18a, a constituent of the 60S ribosomal subunit While the biological significance of this interaction is unclear, it is worth noting that L18a interacts with viral proteins and with initiation factor eIF3 and facilitates internal re-initiation of translation in Cauliflower mosaic virus- and Hepatitis C virus-infected cells 97 — Whether p30 expression may directly or indirectly modulate internal initiation to increase expression of these genes warrants further studies.
The accumulation of several proteins in the nucleoli including Rex and Rev is transcription-dependent , Measurement of GFP-p30 recovery kinetics in response to actinomycin D treatment by fluorescence recovery after photo-bleaching indicated a much slower recovery of fluorescence following actinomycin D treatment This confirms that GFP-p30 is in fact retained in the nucleoli in a transcription-dependent manner via interaction with less-mobile nucleolar components.
Rex interacts with the RXRE and stimulates nuclear export of incompletely spliced viral RNA, thereby increasing production of virus particles. How these two proteins, with apparently opposite functions, integrate in the viral replication cycle is unclear. Using recombinant protein and transient transfection assays, p30 was found to specifically form complexes with Rex in vivo and in vitro A region located between amino acids — of p30 encompasses the Rex binding site Fig.
Mutants of p30 that localized in the nucleus or the nucleolus were both able to interact with Rex, suggesting that these proteins form complexes in the nucleoplasm. Interactions between Rex and p30 were strengthened when co-expressed in the presence of an HTLV-1 molecular clone but not in presence of Tax, suggesting that pRex complexes are stabilized onto viral mRNA This was further confirmed in in vitro experiments in which viral RNA incubated with Rex and p30 increased complex formation, while RNAse had the opposite effect.
A Rex mutant in which six arginines involved in RNA binding have been mutated to lysines RexLys was shown to have the same cellular localization as the wildtype Rex, but to be selectively defective in RNA binding. Studies aimed at understanding the specificity of p30 showed that Rex and p30 differentially associate onto viral mRNA.
These findings can be explained by the fact that Rex has a high affinity for its RXRE, and whenever Rex is bound to RNA, its p30 binding domain is no longer accessible, preventing pRex protein complex formation.
Such a mechanism of regulation allows vigilant control of viral gene expression.
The p30 reduces viral expression to prevent immune detection, but Rex guarantees low basal expression to produce a small amount of Tax essential for the early stages of T-cell transformation and to sustain expression of p30 Fig. Rex and p30 govern the switch between virus latency and replication. Human T-cell lymphotropic virus-1 has evolved multiple strategies to extend the lifespan of infected cells.
This, in turn, allows accumulation of genetic mutations and, with time, disease progression. Because HTLV-1 is very immunogenic and has low variability, reducing its expression is key to virus maintenance in vivo. It is no surprise that HTLV-1 has evolved numerous strategies to limit its own expression.
Tax is a potent transcriptional activator and very immunogenic. Hence, Tax expression needs to be tightly controlled. Tax is generally toxic, inducing multiple cell-cycle defects and apoptosis, in cells that have not yet acquired tolerance. Following initial infection, only cells with low Tax expression are able to survive. Thus, a natural cycle exists for selection of cells with low Tax expression.
Surprisingly, p30 protein also affects the toll-like receptor-4 signaling pathway, suggesting that HTLV-1 subverts a component of the host innate immunity.
Recently, several studies have highlighted the role of HBZ in suppression of Tax expression. National Center for Biotechnology Information , U. AIDS Rev.
Author manuscript; available in PMC Oct 1. Hicham H. Baydoun , Marcia Bellon , and Christophe Nicot. Author information Copyright and License information Disclaimer. Correspondence to: Copyright notice. See other articles in PMC that cite the published article. HTLV-1, Rex. Open in a separate window.
Figure 1. HTLV-1 Rex: Figure 2.
Figure 3. HTLV-1 p Figure 4. Conclusions Human T-cell lymphotropic virus-1 has evolved multiple strategies to extend the lifespan of infected cells. References 1. Adult T-cell leukemia: Take your PDF tools to go. Work on documents anywhere using the Acrobat Reader mobile app. You can use your device camera to capture a document, whiteboard, or receipt and save it as a PDF.
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