Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.22 (cdc2)
 8,319 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Stimulation of primary human T lymphocytes results in up-regulation of cyclin T1 expression, which correlates with phosphorylation of the C-terminal domain of RNA polymerase II (RNAP II). Up-regulation of cyclin T1 and concomitant stabilization of cyclin-dependent kinase 9 (CDK9) may facilitate productive replication of HIV in activated T cells. We report that treatment of PBLs with two mitogens, PHA and PMA, results in accumulation of cyclin T1 via distinct mechanisms. PHA induces accumulation of cyclin T1 mRNA and protein, which results from cyclin T1 mRNA stabilization, without significant change in cyclin T1 promoter activity. Cyclin T1 mRNA stabilization requires the activation of both calcineurin and JNK because inhibition of either precludes cyclin T1 accumulation. In contrast, PMA induces cyclin T1 protein up-regulation by stabilizing cyclin T1 protein, apparently independently of the proteasome and without accumulation of cyclin T1 mRNA. This process is dependent on Ca2+-independent protein kinase C activity but does not require ERK1/2 activation. We also found that PHA and anti-CD3 Abs induce the expression of both the cyclin/CDK complexes involved in RNAP II C-terminal domain phosphorylation and the G1-S cyclins controlling cell cycle progression. In contrast, PMA alone is a poor inducer of the expression of G1-S cyclins but often as potent as PHA in inducing RNAP II cyclin/CDK complexes. These findings suggest coordination in the expression and activation of RNAP II kinases by pathways that independently stimulate gene expression but are insufficient to induce S phase entry in primary T cells.
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PMID:Cyclin T1 expression is regulated by multiple signaling pathways and mechanisms during activation of human peripheral blood lymphocytes. 1627 92

The Positive Transcriptional Elongation Factor b (P-TEFb), a heterodimer of CDK9 and Cyclin T1, is widely implicated in control of basal gene expression. Here, P-TEFb is involved in transitioning paused RNA polymerase II to enter productive transcriptional elongation mode by phosphorylating negative elongation factors and Ser(2) of the heptad repeat in the RNA Pol II COOH terminal domain (CTD). This perspective will examine recent work in two unrelated inducible signaling pathways that illustrate the central role of P-TEFb in mediating cytokine inducible transcription networks. Specifically, P-TEFb has been recently discovered to play a key role in TNF-inducible NFkappaB activation and IL-6-inducible STAT3 signaling. In these signaling cascades, P-TEFb forms protein complexes with the activated nuclear RelA and STAT3 transcription factor in the cellular nucleoplasm, an association important for P-TEFb's promoter targeting. Studies using siRNA-mediated knockdown and/or selective CDK inhibitors show that P-TEFb plays a functional role in activation of a subset of NFkappaB-dependent targets and all STAT3-dependent genes studied to date. Interestingly, cytokine inducible genes that are sensitive to P-TEFb inhibition share an induction mechanism requiring inducible RNA Pol II recruitment. Chromatin immunoprecipitation studies have preliminarily indicated that this recruitment is dependent on CDK enzymatic activity. The potential of inhibiting P-TEFb as an anti-inflammatory therapy in innate immunity and systemic inflammation will be discussed.
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PMID:Expanding role of cyclin dependent kinases in cytokine inducible gene expression. 1872 88

Noncoding RNAs play important roles in various aspects of gene regulation. We have identified 7SK RNA to be enriched in nuclear speckles or interchromatin granule clusters (IGCs), a subnuclear domain enriched in pre-mRNA processing factors. 7SK RNA, in association with HEXIM 1 and 2, is involved in the inhibition of transcriptional elongation by RNA polymerase II. Inhibition occurs via sequestration of the active P-TEFb kinase complex (CDK 9 and Cyclin T1/T2a/b or K) that is involved in phosphorylating the C-terminal domain of RNA polymerase II. Our results demonstrate that knock-down of 7SK RNA, by specific antisense oligonucleotides, results in the mislocalization of nuclear speckle constituents in a transcription-dependent manner, and the transcriptional up-regulation of a RNA polymerase II transcribed reporter gene locus. Furthermore, 7SK RNA transiently associates with a stably integrated reporter gene locus upon transcriptional down-regulation and its presence correlates with the efficient displacement of P-TEFb constituents from the locus. Our results suggest that 7SK RNA plays a role in modulating the available level of P-TEFb upon transcriptional down-regulation by sequestering its constituents in nuclear speckles.
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PMID:Nuclear organization and dynamics of 7SK RNA in regulating gene expression. 2088 Oct 57