Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Here we show that the phosphorylation of histone acetyltransferase Tip60, a target of human immunodeficiency virus, type 1-encoded transactivator Tat, plays a crucial role in the control of its catalytic activity. Baculovirus-based expression and purification of Tip60 combined with mass spectrometry allowed the identification of serines 86 and 90 as two major sites of phosphorylation in vivo. The phosphorylation of Tip60 was found to modulate its histone acetyltransferase activity. One of the identified phosphorylated serines, Ser-90, was within a consensus cyclin B/Cdc2 site. Ser-90 was specifically phosphorylated in vitro by the cyclin B/Cdc2 complex. Accordingly, the phosphorylation of Tip60 was enhanced after drug-induced arrest of cells in G(2)/M. This G(2)/M-dependent phosphorylation of Tip60 was abolished by treating cells with a specific inhibitor of the cyclin-dependent kinase, roscovitin. All together, these results strongly suggest a G(2)/M-dependent control of Tip60 activity.
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PMID:Tip60 acetyltransferase activity is controlled by phosphorylation. 1246 30

A recent consensus conference proposed a new classification for focal segmental glomerulosclerosis (FSGS). Five patterns have been defined: FSGS not otherwise specified, perihilar variant, cellular variant, tip variant, and collapsing variant. In light of the multiplicity of classification schemes in use, the promise of a rational and uniform scheme for FSGS pathology is most welcome. This approach has worked extremely well for the classification of lupus nephritis. It does not necessarily mean, however, that this new classification scheme will help to select treatment protocols according to histopathologic subsets of FSGS. In fact, one renal biopsy examination may show multiple variants and this classification, despite many merits, still lumps categories that should be split and splits categories that should be lumped together. It has become clear that despite its histologic diversity FSGS begins as a podocyte disease that progresses from a cellular to a scar lesion. Recent years have brought about astonishing insight into the complex molecular array of proteins forming the slit diaphragm between podocyte foot processes, a narrow space essential for restricting glomerular permeability to albumin. Concentrating on the podocyte rather than on the glomerular tuft is helpful for abolishing the classic distinction between primary versus secondary forms of FSGS, a distinction that crumbles away with each new evidence of genetic, ischemic, or viral etiologies of FSGS, despite similar lesions. In fact, recent studies focusing on the podocyte changes that occur in various subsets of FSGS have unraveled the striking phenomena of podocyte dedifferentiation and transdifferentiation along with differential expression of cyclin-dependent kinase inhibitors. Interestingly, the latter showed that expression of cyclin-dependent kinase inhibitors p21 and proliferation marker Ki-67 are the same in cellular FSGS, collapsing glomerulopathy, and human immunodeficiency virus-associated FSGS. Taken together these findings lead to a reassuring unitary interpretation of the pluralistic appearance of FSGS by histopathology. Clearly, further studies of the podocyte will lead to improved understanding of FSGS and to improved classification schemes that are grounded in molecular understanding of glomerular injury and that will guide the clinician in the choice of treatment and prognosis.
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PMID:E pluribus unum: The riddle of focal segmental glomerulosclerosis. 1270 73

Positive transcription factor b (P-TEFb) is required for RNA polymerase II to make the transition from abortive to productive elongation. This important factor is a heterodimer of a cyclin-dependent kinase, cyclin-dependent kinase 9 (Cdk9), and one of four cyclin partners, cyclin T1, T2a, T2b or K. We demonstrate here that there exists in cells a second form of Cdk9 that is 13 kDa larger than the protein originally identified. Both of these forms, which we name Cdk9(42) and Cdk9(55), are present in HeLa and NIH/3T3 cells. Cdk9(55) is generated from an mRNA that originates from a second promoter located upstream of the startpoint of transcription used to generate mRNAs encoding Cdk9(42). Antibodies specific for Cdk9(55) immunoprecipitate Cdk(55) and cyclin T1, but not Cdk9(42). Cdk9(55) in the immunoprecipitates is active as judged by its ability to phosphorylate the carboxyl-terminal domain of the largest subunit of RNA polymerase II. Recently it has been shown that the activity of P-TEFb is negatively regulated in cells by reversible association with a small cellular RNA called 7SK. We show here that P-TEFb molecules containing either form of Cdk9 are found in association with 7SK and both complexes are disrupted by treatment with 600 mM KCl. The relative abundance of Cdk9(55) and Cdk9(42) changes in different cell types, including HeLa, NIH/3T3, human macrophages and mouse lung tissue. Additionally, treatment of macrophages with lipopolysaccharides or infection with human immunodeficiency virus alters the relative abundance of the two forms of Cdk9.
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PMID:Identification of a novel isoform of Cdk9. 1270

Cells expressing the envelope glycoprotein complex (Env) encoded by the human immunodeficiency virus can fuse with cells expressing Env receptors (CD4 and CXCR4). The resulting syncytia undergo apoptosis. We developed a cytofluorometric assay for the quantitation of syncytium formation and syncytial apoptosis. Using this methodology, we show that caspase activation in syncytia is inhibited by pharmacological or genetic intervention on cyclin-dependent kinase-1, p53, and mitochondrial membrane permeabilization (MMP). Thus, transfection of fusing cells with the viral mitochondrial inhibitor of apoptosis encoded by cytomegalovirus, a specific inhibitor of MMP, prevented the mitochondrial cytochrome c release and abolished simultaneously the activation of caspase-3. Conversely, inhibition of caspases did not prevent MMP. These results indicate that Env-elicited syncytial apoptosis involves the intrinsic (mitochondrial) pathway.
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PMID:Mitochondrion-dependent caspase activation by the HIV-1 envelope. 1455 4

Some anticancer drugs, but not all, inhibit replication of human immunodeficiency virus (HIV) and thus, exhibit a therapeutic potential. Such drugs, unlike the traditional HIV enzyme inhibitors, could suppress HIV strains that are resistant to inhibitors of viral enzymes, decrease proviral burden in vivo, or reduce reservoirs of infection via killing infected cells. Thus, they may be an effective adjunct therapy or perhaps result in a cure. The incidence of HIV infection and AIDS mortalities continue to increase worldwide, including the United States and parts of Africa, with a parallel increase in a number of other manifestations, including AIDS defining malignancies. The basis for continual spread of HIV presumably in large part stems from the viral resistance to previously successful drugs and the lack of curative antiretroviral drugs. To reverse these trends, other approaches for AIDS therapy must be developed. One possibility is the development of potent anticancer drugs, that exhibit anti-HIV activities. At least four chemically and pharmacologically distinct classes of anticancer drugs, i.e. certain cyclin-dependent kinase inhibitors (CDKIs), topoisomerase 1 enzyme (top 1) inhibitors, non-nucleoside antimetabolites, and estrogen receptor ligands are promising candidates. These drugs, at high doses are used for cancer therapy; at lower concentrations they exhibit anti-HIV activities in cultured cells. While the antiretroviral and the anticancer activities of the cdk inhibitor flavopiridol appear to be mutually exclusive and unrelated in cells and animal model(s) of HIV disease, the top 1 inhibitor 9-nitrocamptothecin, as well as the cdk-inhibitor roscovitine inhibit replication of HIV via selective sensitization of HIV-infected cells to apoptosis. In contrast, the inhibitory effects of these compounds are different from other cancer therapeutics that, at toxic concentrations, activate HIV either in cultured cells (such as certain ingenol and butyrate derivatives) and/or in patients (such as the widely used cyclophosmamide and cisplatin). This quality may lead to the eradication of proviral reservoirs, which is not accomplished by the currently available antiretroviral drugs. In this review, relevant available clinical and in vitro data that either support or discourage using certain anticancer drugs for treatment of HIV disease, and the rationales for developing novel antiretroviral drugs that may target infected cells rather than viral proteins are discussed.
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PMID:A novel approach to develop anti-HIV drugs: adapting non-nucleoside anticancer chemotherapeutics. 1467 May 89

The envelope glycoprotein complex (Env) of human immunodeficiency virus-1 (HIV-1) can induce apoptosis by a cornucopia of distinct mechanisms. A soluble Env derivative, gp120, can kill cells through signals that are transmitted by chemokine receptors such as CXCR4. Cell surface-bound Env (gp120/gp41), as present on the plasma membrane of HIV-1-infected cells, can kill uninfected bystander cells expressing CD4 and CXCR4 (or similar chemokine receptors, depending on the Env variant) by at least three different mechanisms. First, a transient interaction involving the exchange of lipids between the two interacting cells ('the kiss of death') may lead to the selective death of single CD4-expressing target cells. Second, fusion of the interacting cells may lead to the formation of syncytia which then succumb to apoptosis in a complex pathway involving the activation of several kinases (cyclin-dependent kinase-1, Cdk1; checkpoint kinase-2, Chk2; mammalian target of rapamycin, mTOR; p38 mitogen-activated protein kinase, p38 MAPK; inhibitor of NF-kappaB kinase, IKK), as well as the activation of several transcription factors (NF-kappaB, p53), finally resulting in the activation of the mitochondrial pathway of apoptosis. Third, if the Env-expressing cell is at an early stage of imminent apoptosis, its fusion with a CD4-expressing target cell can precipitate the death of both cells, through a process that may be considered as contagious apoptosis and which does not involve Cdk1, mTOR, p38 nor p53, yet does involve mitochondria. Activation of some of the above- mentioned lethal signal transducers have been detected in patients' tissues, suggesting that HIV-1 may indeed trigger apoptosis through molecules whose implication in Env-induced killing has initially been discovered in vitro.
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PMID:Mechanisms of apoptosis induction by the HIV-1 envelope. 1571 26

Astragalus memebranaceus is used as immunomodulating agent in treating immunodeficiency diseases and to alleviate the adverse effects of chemotherapeutic drugs. In recent years, it has been proposed that Astragalus may possess anti-tumorigenic potential in certain cancer cell types. In this study, the anti-carcinogenic effects of Astragalus saponin extract were investigated in HT-29 human colon cancer cells and tumor xenograft. Our findings have shown that Astragalus saponins (AST) inhibit cell proliferation through accumulation in S phase and G2/M arrest, with concomitant suppression of p21 expression and inhibition of cyclin-dependent kinase activity. Besides, AST promotes apoptosis in HT-29 cells through caspase 3 activation and poly(ADP-ribose) polymerase cleavage, which is indicated by DNA fragmentation and nuclear chromatin condensation. Nevertheless, we also demonstrate the anti-tumorigenic effects of AST in vivo, of which the reduction of tumor volume as well as pro-apoptotic and anti-proliferative effects in HT-29 nude mice xenograft are comparable with that produced by the conventional chemotherapeutic drug 5-fluorouracil (5-FU). In addition, the side effects (body weight drop and mortality) associated with the drug combo 5-FU and oxaliplatin are not induced by AST. These results indicate that AST could be an effective chemotherapeutic agent in colon cancer treatment, which might also be used as an adjuvant in combination with other orthodox chemotherapeutic drugs to reduce the side effects of the latter compounds.
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PMID:Astragalus saponins induce growth inhibition and apoptosis in human colon cancer cells and tumor xenograft. 1714 4

Relatively little is known at the functional genomic level about the global host response to human immunodeficiency virus type 1 (HIV-1) infection. Microarray analyses by several laboratories, including our own, have revealed that HIV-1 infection causes significant changes in host mRNA abundance and regulation of several cellular biological pathways. However, it remains unclear what consequences these changes bring about at the protein level. Here we report the expression levels of approximately 3,200 proteins in the CD4(+) CEMx174 cell line after infection with the LAI strain of human immunodeficiency virus type 1 (HIV-1); the proteins were assessed using liquid chromatography-mass spectrometry coupled with stable isotope labeling and the accurate mass and time tag approach. Furthermore, we found that 687 (21%) proteins changed in abundance at the peak of virus production at 36 h postinfection. Pathway analysis revealed that the differential expression of proteins was concentrated in select biological pathways, exemplified by ubiquitin-conjugating enzymes in ubiquitination, carrier proteins in nucleocytoplasmic transport, cyclin-dependent kinase in cell cycle progression, and pyruvate dehydrogenase of the citrate cycle pathways. Moreover, we observed changes in the abundance of proteins with known interactions with HIV-1 viral proteins. Our proteomic analysis captured changes in the host protein milieu at the time of robust virus production, depicting changes in cellular processes that may contribute to virus replication. Continuing analyses are expected to focus on blocking virus replication by targeting these pathways and their effector proteins.
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PMID:Quantitative analysis of human immunodeficiency virus type 1-infected CD4+ cell proteome: dysregulated cell cycle progression and nuclear transport coincide with robust virus production. 1749 70

The human immunodeficiency virus type 1 (HIV-1) Tat is a 14-kDa viral protein that acts as a potent transactivator by binding to the transactivation-responsive region, a structured RNA element located at the 5' end of all HIV-1 transcripts. Tat transactivates viral gene expression by inducing the phosphorylation of the C-terminal domain of RNA polymerase II through several Tat-activated kinases and by recruiting chromatin-remodeling complexes and histone-modifying enzymes to the HIV-1 long terminal repeat. Histone acetyltransferases, including p300 and hGCN5, not only acetylate histones but also acetylate Tat at lysine positions 50 and 51 in the arginine-rich motif. Acetylated Tat at positions 50 and 51 interacts with a specialized protein module, the bromodomain, and recruits novel factors having this particular domain, such as P/CAF and SWI/SNF. In addition to having its effect on transcription, Tat has been shown to be involved in splicing. In this study, we demonstrate that Tat interacts with cyclin-dependent kinase 13 (CDK13) both in vivo and in vitro. We also found that CDK13 increases HIV-1 mRNA splicing and favors the production of the doubly spliced protein Nef. In addition, we demonstrate that CDK13 acts as a possible restriction factor, in that its overexpression decreases the production of the viral proteins Gag and Env and subsequently suppresses virus production. Using small interfering RNA against CDK13, we show that silencing of CDK13 leads to a significant increase in virus production. Finally, we demonstrate that CDK13 mediates its effect on splicing through the phosphorylation of ASF/SF2.
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PMID:CDK13, a new potential human immunodeficiency virus type 1 inhibitory factor regulating viral mRNA splicing. 1848 Apr 52

The positive transcription elongation factor (P-TEFb) consists of CDK9, a cyclin-dependent kinase and its cyclin T partner. It is required for transcription of most class II genes. Its activity is regulated by non-coding RNAs. The 7SK cellular RNA turns the HEXIM cellular protein into a P-TEFb inhibitor that binds its cyclin T subunit. Thus, P-TEFb activity responds to variations in global cellular transcriptional activity and to physiological conditions linked to cell differentiation, proliferation or cardiac hypertrophy. In contrast, the Tat activation region RNA plays an activating role. This feature at the 5' end of the human immunodeficiency (HIV) viral transcript associates with the viral protein Tat that in turn binds cyclin T1 and recruits active P-TEFb to the HIV promoter. This results in enhanced P-TEFb activity, which is critical for an efficient production of viral transcripts. Although discovered recently, the regulation of P-TEFb becomes a paradigm for non-coding RNAs that regulate transcription factors. It is also a unique example of RNA-driven regulation of a cyclindependent kinase.
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PMID:RNA-driven cyclin-dependent kinase regulation: when CDK9/cyclin T subunits of P-TEFb meet their ribonucleoprotein partners. 1870 41


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