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)

The ubiquitous transcription factor, NF-Y, plays a pivotal role in the cell cycle regulation of the mammalian cyclin A, cdc25C, and cdc2 genes, in the S-phase activation of the ribonucleotide reductase R2 gene, in addition to its critical role as a key proximal promoter factor in the transcriptional regulation of the albumin, collagen, lipoprotein lipase, major histocompatibility complex class II, and a variety of other eukaryotic and viral genes. In this report, the NF-Y complex has been shown to possess histone acetyltransferase activity through physical association with the related histone acetyltransferase enzymes, human GCN5 and P/CAF in vivo. The assembled NF-YA:B:C complex, and the NF-YB:YC, NF-YB:YC (DNA binding-subunit interaction domain), and NF-YC:YB (DNA binding-subunit interaction domain) heterodimers were sufficient to support stable interaction with human GCN5 in vitro, suggesting that these histone acetyltransferases interact with a unique surface in the ancient YB:YC histone-fold motif. Deletion of either N- or C-terminal regions in human GCN5 disrupted interaction with NF-Y in vitro. In addition, human GCN5 was observed to activate NF-Y in transient transfections in vivo using a natural alpha 2(I) collagen promoter. These results suggest that these associated histone acetyltransferases may serve to modulate NF-Y transactivation potential by aiding disruption of local chromatin structure thereby facilitating NF-Y access to its CCAAT box DNA binding sites.
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PMID:NF-Y is associated with the histone acetyltransferases GCN5 and P/CAF. 943 Jun 79

Activation of the transcription unit early region 2 (E2) promoter of the oncogenic adenovirus serotype 12 (Ad12), which regulates the expression of proteins essential for viral replication, requires the assembly of a ternary complex consisting of cAMP response element-binding protein (CREB)-1/activating transcription factor (ATF)-1, the Ad12 12S oncogene product of early region 1A (E1A(12S)), and the co-activator p300/CBP on the E2(Ad12) cAMP response element (E2-CRE). Here we show that the active E2(Ad12) promoter is associated with acetylated histone H4 whereas an E2-CRE point-mutated promoter which is transcriptionally inactive due to its inability to assemble this ternary complex is not bound by acetylated histone H4. The histone deacetylase 1 as well as Roscovitine, which blocks the activation of the histone acetyltransferase (HAT) activity of CBP by cyclin E-Cdk2, prevents E2(Ad12) promoter activation through E1A(12S). p300/CBP counteracts the repressive function of histone deacetylase 1 in a HAT domain-dependent manner whereas the p300/CBP-associated factor PCAF failed to rescue E2(Ad12) promoter activity. E1A(12S) bound p300/CBP displays strong HAT activity. Most interestingly, E1A(12S)-mediated activation of the E2(Ad12) promoter correlates well with the ability of the viral protein to associate with the HAT activity of p300/CBP in vivo. Taken together these data indicate that the recruitment of the HAT activity of p300/CBP by E1A(12S) plays an important role in E2(Ad12) promoter activation.
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PMID:E1A12S-mediated activation of the adenovirus type 12 E2 promoter depends on the histone acetyltransferase activity of p300/CBP. 1100 73

The transactivation/transformation-domain associated protein (TRRAP) belongs to the Ataxia-telangiectasia mutated (ATM) super-family and has been identified as a cofactor for c-MYC-mediated oncogenic transformation. TRRAP and its yeast homolog (Tra1p) are components of histone acetyltransferase (HAT) complexes, SAGA (refs. 2,4,5), PCAF (ref. 3) and NuA4 (ref. 6), which are important for the regulation of transcription and cell cycle progression and also have a role in cell viability. Yet the biological function of this molecule and how it controls proliferation are still unclear. Here we show that null mutation of Trrap in mice results in peri-implantation lethality due to a blocked proliferation of blastocysts. We use an inducible Cre-loxP system to show that loss of Trrap blocks cell proliferation because of aberrant mitotic exit accompanied by cytokinesis failure and endoreduplication. Trrap-deficient cells fail to sustain mitotic arrest despite chromosome missegregation and disrupted spindles, and display compromised cdk1 activity. Trrap is therefore essential for early development and required for the mitotic checkpoint and normal cell cycle progression.
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PMID:Disruption of Trrap causes early embryonic lethality and defects in cell cycle progression. 1154 77

Cell cycle activation is coordinated by D-type cyclins which are rate limiting and essential for the progression through the G1 phase of the cell cycle. D-type cyclins bind to and activate the cyclin-dependent kinases Cdk4 and Cdk6, which in turn phosphorylate their downstream target, the retinoblastoma protein Rb. Upon Rb phosphorylation, the E2F transcription factors activate the expression of S-phase genes and thereby induce cell cycle progression. The raise of cyclin D levels in early G1 also serves to titrate Kip/Cip proteins away from cyclinE/Cdk2 complexes, further accelerating cell cycle progression. Therefore, cyclin D plays essential roles in the response to mitogens, transmitting their signal to the Rb/E2F pathway. Surprisingly, cyclin D1-deficient animals are viable and have developmental abnormalities limited to restricted tissues, such as retina, the nervous system and breast epithelium. This observation, combined with several other studies, have raised the possibility that cyclin D1 may have new activities that are unrelated to its function as a cdk regulatory subunit and as regulator of Rb. Effectively, cyclin D has been reported to have transcriptional functions since it interacts with several transcription factors to regulate their activity. Most often, this effect does not rely on the kinase function of Cdk4, indicating that this function is probably independent of cell cycle progression. Further extending its role in gene regulation, cyclin D interacts with histone acetylases such as P/CAF or NcoA/SRC1a but also with components of the transcriptional machinery such as TAF(II)250. Therefore, these studies suggest that the functions of cyclin D might need to be reevaluated. They have established a new cdk-independent role of cyclin D1 as a transcriptional regulator, indicating that cyclin D1 can act via two different mechanisms, as a cdk activator it regulates cell cycle progression and as a transcriptional regulator, it modulates the activity of transcription factors.
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PMID:Linking cyclins to transcriptional control. 1245 51

During skeletal myogenesis, muscle-regulatory factors bHLH and MEF2 promote the expression of muscle-specific genes by recruiting several chromatin-modifying complexes on specific DNA regulatory sequences. A number of MyoD-interacting proteins have been reported, but whether they are recruited to the chromatin of myogenic loci, and the relationship with other chromatin bound proteins is unknown. We show that MyoD recruits cdk9/cyclin T2, together with the histone acetyltransferases p300 and PCAF, and the chromatin remodeling complex SWI/SNF, on promoters and enhancers of muscle-specific genes, and that this event correlates with the acetylation of histone tails, remodeling of chromatin, and phosphorylation of the C-terminal domain (CTD) of the RNA polymerase II at these elements.
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PMID:MyoD recruits the cdk9/cyclin T2 complex on myogenic-genes regulatory regions. 1624 9

The emergence of drug-resistant HIV-1 strains presents a challenge for the design of new therapy. Targeting host cell factors that regulate HIV-1 replication might be one way to overcome the propensity for HIV-1 to mutate in order to develop resistance to antivirals. This article reviews the interplay between viral proteins Tat and Rev and their cellular cofactors in the transcriptional and post-transcriptional regulation of HIV-1 gene expression. HIV-1 Tat regulates viral transcription by recruiting cellular factors to the HIV promoter. Tat interacts with protein kinase complexes Cdk9/cyclin T1 and Cdk2/cyclin E; acetyltransferases p300/CBP, p300/CBP-associated factor and hGCN5; protein phosphatases and other factors. HIV-1 Rev regulates post-transcriptional processing of viral mRNAs. Rev primarily functions to export unspliced and partially spliced viral RNAs from the nucleus into the cytoplasm. For this activity, Rev cooperates with cellular transport protein CRM1 and RNA helicases DDX1 and DDX3, amongst others.
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PMID:Transcriptional and post-transcriptional regulation of HIV-1 gene expression: role of cellular factors for Tat and Rev. 1766 32

FOXM1c transactivates the c-myc promoter by binding directly to its TATA-boxes. The present study demonstrates that the transactivation of the c-myc promoter by FOXM1c is enhanced by the key proliferation signal cyclin E/Cdk2, but repressed by P/CAF and the adenoviral oncoprotein E1A. Furthermore, FOXM1c interacts with the coactivator and histone acetyltransferase P/CAF. This study shows that, on the c-myc-P1 TATA-box, FOXM1c does not function simply as normal transcription factor just binding to an unusual site. Moreover, the inhibitory N-terminus of FOXM1c does not inhibit its transrepression domain or its EDA. Others reported that a cyclin/Cdk-binding LXL-motif of the splice variant FoxM1b is required for its interaction with Cdk2, Cdk1, and p27, its phosphorylation by Cdk1 and its activation by Cdc25B. In contrast, we now demonstrate that this LXL-motif is not required for the activation of FOXM1c by cyclin D1/Cdk4, cyclin E/Cdk and cyclin A/Cdk2 or for the repression of FOXM1c by p27.
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PMID:Cyclin E/Cdk2, P/CAF, and E1A regulate the transactivation of the c-myc promoter by FOXM1. 1820 47

Promoter clearance and transcriptional processivity in eukaryotic cells are fundamentally regulated by the phosphorylation of the carboxy-terminal domain of RNA polymerase II (RNAPII). One of the kinases that essentially performs this function is P-TEFb (positive transcription elongation factor b), which is composed of cyclin-dependent kinase 9 (CDK9) associated with members of the cyclin T family. Here we show that cellular GCN5 and P/CAF, members of the GCN5-related N-acetyltransferase family of histone acetyltransferases, regulate CDK9 function by specifically acetylating the catalytic core of the enzyme and, in particular, a lysine that is essential for ATP coordination and the phosphotransfer reaction. Acetylation markedly reduces both the kinase function and transcriptional activity of P-TEFb. In contrast to unmodified CDK9, the acetylated fraction of the enzyme is specifically found in the insoluble nuclear matrix compartment. Acetylated CDK9 associates with the transcriptionally silent human immunodeficiency virus type 1 provirus; upon transcriptional activation, it is replaced by the unmodified form, which is involved in the elongating phase of transcription marked by Ser2-phosphorylated RNAPII. Given the conservation of the CDK9 acetylated residues in the catalytic task of virtually all CDK proteins, we anticipate that this mechanism of regulation might play a broader role in controlling the function of other members of this kinase family.
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PMID:Acetylation of conserved lysines in the catalytic core of cyclin-dependent kinase 9 inhibits kinase activity and regulates transcription. 1825 Jan 57

The human Mediator complex is generally required for expression of protein-coding genes. Here, we show that the GCN5L acetyltransferase stably associates with Mediator together with the TRRAP polypeptide. Yet, contrary to expectations, TRRAP/GCN5L does not associate with the transcriptionally active core Mediator but rather with Mediator that contains the cdk8 subcomplex. Consequently, this derivative 'T/G-Mediator' complex does not directly activate transcription in a reconstituted human transcription system. However, within T/G-Mediator, cdk8 phosphorylates serine-10 on histone H3, which in turn stimulates H3K14 acetylation by GCN5L within the complex. Tandem phosphoacetylation of H3 correlates with transcriptional activation, and ChIP assays demonstrate co-occupancy of T/G-Mediator components at several activated genes in vivo. Moreover, cdk8 knockdown causes substantial reduction of global H3 phosphoacetylation, suggesting that T/G-Mediator is a major regulator of this H3 mark. Cooperative H3 modification provides a mechanistic basis for GCN5L association with cdk8-Mediator and also identifies a biochemical means by which cdk8 can indirectly activate gene expression. Indeed our results suggest that T/G-Mediator directs early events-such as modification of chromatin templates-in transcriptional activation.
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PMID:Cooperative activity of cdk8 and GCN5L within Mediator directs tandem phosphoacetylation of histone H3. 1841 85

Cyclin dependent kinases (cdks) regulate cell cycle progression and transcription. We report here that the transcriptional co-activator PCAF directly interacts with cdk2. This interaction is mainly produced during S and G(2)/M phases of the cell cycle. As a consequence of this association, PCAF inhibits the activity of cyclin/cdk2 complexes. This effect is specific for cdk2 because PCAF does not inhibit either cyclin D3/cdk6 or cyclin B/cdk1 activities. The inhibition is neither competitive with ATP, nor with the substrate histone H1 suggesting that somehow PCAF disturbs cyclin/cdk2 complexes. We also demonstrate that overexpression of PCAF in the cells inhibits cdk2 activity and arrests cell cycle progression at S and G(2)/M. This blockade is dependent on cdk2 because it is rescued by the simultaneous overexpression of this kinase. Moreover, we also observed that PCAF acetylates cdk2 at lysine 33. As this lysine is essential for the interaction with ATP, acetylation of this residue inhibits cdk2 activity. Thus, we report here that PCAF inhibits cyclin/cdk2 activity by two different mechanisms: (i) by somehow affecting cyclin/cdk2 interaction and (ii) by acetylating K33 at the catalytic pocket of cdk2. These findings identify a previously unknown mechanism that regulates cdk2 activity.
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PMID:The transcriptional co-activator PCAF regulates cdk2 activity. 1977 23


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