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)

Human myeloid leukemia cells, such as HL60, U937, and THP1 cells, undergo macrophage differentiation and growth arrest following treatment with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA). Surprisingly, we find that growth of a significant percentage of THP1 cells is arrested in the G2 phase of the cell cycle. G2 arrest correlates with cell-specific repression of the gene encoding p34cdc2, a crucial regulator of G2/M progression. Intriguingly, TPA-mediated repression of the cdc2 promoter was independent of the transcription factor E2F, distinguishing this pathway from mechanisms responsible for repression of cdc2 transcription in response to serum starvation. The region of the cdc2 promoter required for repression was located from bp -22 to -2 from the major transcriptional start site. This sequence, which we term the R box, directs the uncoupling of the basal promoter from upstream activators following TPA treatment. Analysis of THP1 nuclear proteins revealed a 55-kDa protein that was induced by TPA and interacted with the cdc2 promoter in an R-box-dependent manner. These observations provide evidence for the existence of cell-type- and promoter-specific pathways for the assembly of stable transcriptional initiation complexes that function to differentially regulate the expression of cell cycle control genes in mammalian cells.
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PMID:Identification of a cell-type-specific and E2F-independent mechanism for repression of cdc2 transcription. 776 Aug 24

Ehrlichia chaffeensis is an obligatory intracellular bacterium which resides in an early endosome in monocytes. E. chaffeensis infection in a human monocyte cell line (THP1) significantly altered the transcriptional levels of 4.5% of host genes, including those coding for apoptosis inhibitors, proteins regulating cell differentiation, signal transduction, proinflammatory cytokines, biosynthetic and metabolic proteins, and membrane trafficking proteins. The transcriptional profile of the host cell revealed key themes in the pathogenesis of Ehrlichia. First, E. chaffeensis avoided stimulation of or repressed the transcription of cytokines involved in the early innate immune response and cell-mediated immune response to intracellular microbes, such as the interleukin-12 (IL-12), IL-15, and IL-18 genes, which might make Ehrlichia a stealth organism for the macrophage. Second, E. chaffeensis up-regulated NF-kappaB and apoptosis inhibitors and differentially regulated cell cyclins and CDK expression, which may enhance host cell survival. Third, E. chaffeensis also inhibited the gene transcription of RAB5A, SNAP23, and STX16, which are involved in membrane trafficking. By comparing the transcriptional response of macrophages infected with other bacteria and that of macrophages infected with E. chaffeensis, we have identified few genes that are commonly induced and no commonly repressed genes. These results illustrate the stereotyped macrophage response to other pathogens, in contrast with the novel host response to obligate intracellular Ehrlichia, whose survival depends entirely on a long evolutionary process of outmaneuvering macrophages.
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PMID:Survival strategy of obligately intracellular Ehrlichia chaffeensis: novel modulation of immune response and host cell cycles. 1468 31

SAMHD1 restricts HIV-1 replication in myeloid and quiescent CD4(+) T cells. Here, we show that SAMHD1 restriction activity is regulated by phosphorylation. SAMHD1 interacts with cyclin A2/cdk1 only in cycling cells. Cyclin A2/CDK1 phosphorylates SAMHD1 at the Threonine 592 residue both in vitro and in vivo. Phosphorylation of SAMHD1 Thr592 correlates with loss of its ability to restrict HIV-1. Indeed, while PMA treatment of proliferating THP1 cells results in reduced Thr592 phosphorylation, activation of resting peripheral blood mononuclear cells (PBMCs) and purified quiescent CD4(+) T cells results in increased phosphorylation of SAMHD1 Thr592. Interestingly, we found that treatment of cells by type 1 interferon reduced Thr592 phosphorylation, reinforcing the link between the phosphorylation of SAMHD1 and its antiviral activity. Unlike wild-type SAMHD1, a phosphorylation-defective mutant was able to restrict HIV-1 replication in both PMA-treated and untreated cells. Our results uncover the phosphorylation of SAMHD1 at Thr592 by cyclin A2/CDK1 as a key regulatory mechanism of its antiviral activity.
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PMID:Phosphorylation of SAMHD1 by cyclin A2/CDK1 regulates its restriction activity toward HIV-1. 2360 54