Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.22 (cdc2)
8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite intensive investigation, no clearly defined mechanism explaining human immunodeficiency virus (HIV)-induced cell killing has emerged. HIV-1 infection is initiated through a high-affinity interaction between the HIV-1 external envelope glycoprotein (gp120) and the CD4 receptor on T cells. Cell killing is a later event intimately linked by in vitro genetic analyses with the fusogenic properties of the HIV envelope glycoprotein gp120 and transmembrane glycoprotein gp41. In this report, we describe aberrancies in cell cycle regulatory proteins initiated by cell-cell contact between T cells expressing HIV-1 envelope glycoproteins and other T cells expressing CD4 receptors. Cells rapidly accumulate cyclin B protein and tyrosine-hyperphosphorylated p34cdc2 (cdk1) kinase, indicative of cell cycle arrest at G2 phase. Moreover, these cells continue to synthesize cyclin B protein, enlarge and display an abnormal ballooned morphology, and disappear from the cultures in a pattern previously described for cytotoxicity induced by DNA synthesis (S phase) inhibitors. Similar changes are observed in peripheral blood mononuclear cells infected in vitro with pathogenic primary isolates of HIV-1.
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PMID:Human immunodeficiency virus 1 envelope-initiated G2-phase programmed cell death. 852 69

The product of the human immunodeficiency virus type 1 (HIV-1) vpr gene induces cell cycle arrest in the G2 phase of the cell cycle and is characterized by an accumulation of the hyperphosphorylated form of cdc2 kinase. This phenotype is similar to the effect of DNA-damaging agents, which can also cause cells to arrest at G2. We previously reported that Vpr mimicked some of the effects of a DNA alkylating agent known as nitrogen mustard (HN2). Here we extend these earlier observations by further comparing the activation state of cdc2 kinase, the kinetics of G2 arrest, and the ability to reverse the arrest with chemical compounds known as methylxanthines. Infection of cells synchronized in the G1 phase of the cell cycle with a pseudotyped HIV-1 resulted in arrest at G2 within 12 h postinfection, before the first mitosis. Similar to that induced by HN2, Vpr-induced arrest led to a decrease in cdc2 kinase activity. Vpr-mediated G2 arrest was alleviated by methylxanthines at concentrations similar to those needed to reverse the G2 arrest induced by HN2, and cells proceeded apparently normally through at least one complete cell cycle. These results are consistent with the hypothesis that Vpr induces G2 arrest through pathways that are similar to those utilized by DNA-damaging agents.
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PMID:Human immunodeficiency virus type 1 vpr gene induces phenotypic effects similar to those of the DNA alkylating agent, nitrogen mustard. 909 73

The Vpr gene of human immunodeficiency virus type 1 and type 2 (HIV-1, HIV-2) and simian immunodeficiency virus (SIV) encodes a small nuclear protein which is virion-associated and assists nuclear transport of the preintegration complex. Expression of HIV-1 Vpr has been shown to induce differentiation and prevent proliferation of human cells. HIV-1 Vpr has also been shown to arrest cell growth and cause morphological defects in yeast. In contrast, the Vpx gene of HIV-2 and SIV, which shares sequence homology with Vpr, does not seem to inhibit proliferation of human cells. It has been suggested that the cell cycle arrest effect of Vpr and Vpx is species and cell-type dependent. In this study, we have taken advantage of a conditional expression system to characterize the growth inhibitory effects of Vpr and Vpx of HIV-1, HIV-2, and SIV in the fission yeast Schizosaccharomyces pombe. Our results show that both Vpr and/or Vpx of HIV-1, HIV-2, and SIV arrest cell growth in S. pombe, and HIV-1 Vpr is more cytotoxic than HIV-2 or SIV Vpr or Vpx. Flow cytometry analysis indicated that yeast cells cease proliferating with DNA contents indicative of arrest in G1 and G2, with some cells showing signs of overreplication of DNA. While the observed cell cycle arrest phenotype was not identical to that observed in mammalian cells, there were similarities of growth arrest phenotype caused by Vpr and Vpx in yeast and mammalian cells. Specifically, the observation that yeast and mammalians cell both arrest in G2 with reduced p34/cdc2 kinase activity indicates that Vpr and Vpx interact with conserved target(s) in yeast and mammalian cells. The ability to use genetic analysis to elucidate the mechanisms involved makes S. pombe an excellent model system in which to study the effects of Vpr and Vpx on cellular function.
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PMID:Cell cycle inhibitory effects of HIV and SIV Vpr and Vpx in the yeast Schizosaccharomyces pombe. 912 66

The human cdc2-related kinase PITALRE is the catalytic component of TAK, the Tat-associated kinase. Previously, we have proposed that TAK is a cellular factor that mediates Tat transactivation function. Here we demonstrate that transient overexpression of PITALRE specifically squelches Tat-1 activation of both a transfected and an integrated human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR), suggesting that PITALRE mediates Tat function as a multiprotein complex. A catalytic mutant of PITALRE, D167N, was found to be more efficient than wild-type PITALRE in squelching Tat transactivation. Neither wild-type PITALRE nor D167N was able to squelch transactivation of the human T-cell leukemia type 1 LTR by the Tax protein. Additionally, we show that artificial targeting of PITALRE to a nascent RNA element, in the absence of Tat, activated HIV-1 LTR expression. These results indicate that a PITALRE-containing complex mediates transactivation by Tat and suggest that Tat proteins function by localizing such a PITALRE-containing complex to the site of the transcribing provirus.
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PMID:PITALRE, the catalytic subunit of TAK, is required for human immunodeficiency virus Tat transactivation in vivo. 955 39

Accessory protein Vpr of human immunodeficiency virus type 1 (HIV-1) arrests cell cycling at G(2)/M phase in human and simian cells. Recently, it has been shown that Vpr also causes cell cycle arrest in the fission yeast Schizosaccharomyces pombe, which shares the cell cycle regulatory mechanisms with higher eukaryotes including humans. In this study, in order to identify host cellular factors involved in Vpr-induced cell cycle arrest, the ability of Vpr to cause elongated cellular morphology (cdc phenotype) typical of G(2)/M cell cycle arrest in wild-type and various mutant strains of S. pombe was examined. Our results indicated that Vpr caused the cdc phenotype in wild-type S. pombe as well as in strains carrying mutations, such as the cdc2-3w, Deltacdc25, rad1-1, Deltachk1, Deltamik1, and Deltappa1 strains. However, other mutants, such as the cdc2-1w, Deltawee1, Deltappa2, and Deltarad24 strains, failed to show a distinct cdc phenotype in response to Vpr expression. Results of these genetic studies suggested that Wee1, Ppa2, and Rad24 might be required for induction of cell cycle arrest by HIV-1 Vpr. Cell proliferation was inhibited by Vpr expression in all of the strains examined including the ones that did not show the cdc phenotype. The results supported the previously suggested possibility that Vpr affects the cell cycle and cell proliferation through different pathways.
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PMID:Genetic studies with the fission yeast Schizosaccharomyces pombe suggest involvement of wee1, ppa2, and rad24 in induction of cell cycle arrest by human immunodeficiency virus type 1 Vpr. 1068 78

Productive high-titer infection by human immunodeficiency virus type 1 (HIV-1) requires the activation of target cells. Infection of quiescent peripheral CD4 lymphocytes by HIV-1 results in incomplete, labile reverse transcripts and lack of viral progeny formation. An interplay between Tat and p53 has previously been reported, where Tat inhibited the transcription of the p53 gene, which may aid in the development of AIDS-related malignancies, and p53 expression inhibited HIV-1 long terminal repeat transcription. Here, by using a well-defined and -characterized stress signal, gamma irradiation, we find that upon gamma irradiation, HIV-1-infected cells lose their G(1)/S checkpoints, enter the S phase inappropriately, and eventually apoptose. The loss of the G(1)/S checkpoint is associated with a loss of p21/Waf1 protein and increased activity of a major G(1)/S kinase, namely, cyclin E/cdk2. The p21/Waf1 protein, a known cyclin-dependent kinase inhibitor, interacts with the cdk2/cyclin E complex and inhibits progression of cells into S phase. We find that loss of the G(1)/S checkpoint in HIV-1-infected cells may in part be due to Tat's ability to bind p53 (a known activator of the p21/Waf1 promoter) and sequester its transactivation activity, as seen in both in vivo and in vitro transcription assays. The loss of p21/Waf1 in HIV-1-infected cells was specific to p21/Waf1 and did not occur with other KIP family members, such as p27 (KIP1) and p57 (KIP2). Finally, the advantage of a loss of the G(1)/S checkpoint for HIV-1 per se may be that it pushes the host cell into the S phase, which may then allow subsequent virus-associated processes, such as RNA splicing, transport, translation, and packaging of virion-specific genes, to occur.
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PMID:Loss of G(1)/S checkpoint in human immunodeficiency virus type 1-infected cells is associated with a lack of cyclin-dependent kinase inhibitor p21/Waf1. 1079 78

The Vpr protein of primate lentiviruses arrests cell cycling at the G(2)/M phase through an inactivation of cyclin B-p34(cdc2) and its upstream regulator cdc25. We provide here biochemical and functional evidence demonstrating that human immunodeficiency virus type 1 (HIV-1) Vpr mediates G(2) arrest by forming a complex with protein phosphatase 2A (PP2A), an upstream regulator of cdc25. Vpr associates with PP2A through a specific interaction with the B55 regulatory subunit. This interaction is necessary but not sufficient for G(2) arrest. Interestingly, we found that Vpr association with B55-containing PP2A targets the enzymatic complex to the nucleus and, importantly, enhances the recruitment and dephosphorylation of the cdc25 substrate. Our data suggest that Vpr mediates G(2) arrest by enhancing the nuclear import of PP2A and by positively modulating its catalytic activity towards active phosphorylated nuclear cdc25.
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PMID:Human immunodeficiency virus type 1 Vpr-mediated G(2) cell cycle arrest: Vpr interferes with cell cycle signaling cascades by interacting with the B subunit of serine/threonine protein phosphatase 2A. 1211 Jun 3

Human immunodeficiency virus (HIV)-infection is characterized by loss of CD4+ T cells associated with high levels of immune activation, T-cell proliferation, and lymphocyte apoptosis. To investigate the role of intrinsic perturbations of cell-cycle control in the immunopathogenesis of acquired immunodeficiency syndrome (AIDS), we studied the expression of cell-cycle-dependent proteins in lymphocytes from HIV-infected patients. Cyclin B1 expression, Nucleolar Organizer Regions (NORs) number, and NORs area of distribution were all consistently increased in HIV-infected patients, but returned to normal after effective antiretroviral therapy, suggesting that viral replication is directly implicated in the genesis of the observed changes. Analysis of cyclin B1 intracellular turnover showed that the increased cyclin B1 expression is (1) caused by defective degradation in the presence of normal rates of synthesis, and (2) is temporally associated with decreased levels of ubiquitination. After in vitro activation of lymphocytes from healthy individuals, cyclin B1 and cdc25 expression and ubiquitination, p34 cdc2 activity, NORs morphology, and C23/nucleolin localization showed a 72- to 96-hour cyclic pattern that led to a biologic state similar to baseline. On the contrary, complex but consistent changes of the same indices followed activation of T lymphocytes from HIV-infected patients, resulting in a 5-fold increase in apoptosis. Overall, our data indicate that a profound dysregulation of cell-cycle control is present in lymphocytes from HIV-infected patients. This finding may provide a novel biologic link between immune activation, accelerated lymphocyte turnover, and increased apoptosis during HIV infection.
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PMID:Abnormal intracellular kinetics of cell-cycle-dependent proteins in lymphocytes from patients infected with human immunodeficiency virus: a novel biologic link between immune activation, accelerated T-cell turnover, and high levels of apoptosis. 1123 18

Cyclin T1 was recently identified, together with cdk9 (previously named PITALRE), as part of the TAK multiprotein complex, a co-factor targeted by the human immunodeficiency virus Type 1 (HIV-1) protein named Tat, suggesting a role for this complex in transcription elongation. Although studies on mRNA and protein expression have shown that cyclin T1 is ubiquitous in adult human tissues, no data have yet been reported regarding the expression of this protein in different cell lineages. Using a polyclonal antiserum raised against cyclin T1, we investigated the pattern of expression of this protein in adult human tissues by immunohistochemistry. Cyclin T1 was expressed ubiquitously, although different levels of expression were found in various organs. Some specialized tissues, such as blood, lymphoid tissues, and cells of connective tissue origin, showed high cyclin T1 expression. These specific expression patterns are only partially justified by some well-known specialized functions of cyclin T1 in certain cell types, such as its involvement in peripheral blood lymphocytes and monocyte differentiation. The high expression level found in other tissues suggests new possible roles for cyclin T1 in cell types other than those of lymphoid tissue.
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PMID:Pattern of expression of cyclin T1 in human tissues. 1137 15

The Vpr gene of human immunodeficiency virus type 1 (HIV-1) encodes a 14-kDa protein that prevents cell proliferation by causing arrest in the G2/M phase of the cell cycle. Here we report the first evidence that Vpr activates the expression and transcription of the cyclin-dependent kinase inhibitor p21/Waf1/Cip1 (hereafter p21), an inhibitor of the G1 and G2/M phase transitions in T lymphoid and myeloid cells. Vpr activated p21 protein expression in a dose-dependent manner. Vpr also caused a three- to eightfold induction of the p21 promoter. This induction was dose- and time-dependent and was comparable to levels of p21 induction induced by p53. Of note, Vpr activated p21 transcription in endogenous p53 positive cells, but not in p53-deleted or p53 nonfunctional cells. Vpr and p53 had an additive effect on p21 transcription. Mutational analysis indicated that wt Vpr, but not cell cycle inactive Vpr mutants, activated the p21 promoter. These data demonstrate that HIV-1 Vpr utilizes the cyclin-dependent kinase inhibitor p21, in addition to cdc2, to arrest cells in G2/M.
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PMID:HIV-1 Vpr activates cell cycle inhibitor p21/Waf1/Cip1: a potential mechanism of G2/M cell cycle arrest. 1257 82


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