Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Octamer binding transcription factors (Oct factors) play important roles in activation of transcription of various genes but, in some cases, require cofactors that interact with the DNA binding (POU) domain. In the present study, a yeast two-hybrid screen with the Oct-1 POU domain as a bait identified MAT1 as a POU domain-binding protein. MAT1 is known to be required for the assembly of cyclin-dependent kinase (CDK)-activating kinase (CAK), which is functionally associated with the general transcription factor IIH (TFIIH). Further analyses showed that MAT1 interacts with POU domains of Oct-1, Oct-2, and Oct-3 in vitro in a DNA-independent manner. MAT1-containing TFIIH was also shown to interact with POU domains of Oct-1 and Oct-2. MAT1 is shown to enhance the ability of a recombinant CDK7-cyclin H complex (bipartite CAK) to phosphorylate isolated POU domains, intact Oct-1, and the C-terminal domain of RNA polymerase II, but not the originally defined substrate, CDK2. Phosphopeptide mapping indicates that the site (Ser385) of a mitosis-specific phosphorylation that inhibits Oct-1 binding to DNA is not phosphorylated by CAK. However, one CAK-phosphorylated phosphopeptide comigrates with a Cdc2-phosphorylated phosphopeptide previously shown to be mitosis-specific, suggesting that, in vitro, CAK is able to phosphorylate at least one site that is also phosphorylated in vivo. These results suggest (i) that interactions between POU domains and MAT1 can target CAK to Oct factors and result in their phosphorylation, (ii) that MAT1 not only functions as a CAK assembly factor but also acts to alter the spectrum of CAK substrates, and (iii) that a POU-MAT1 interaction may play a role in the recruitment of TFIIH to the preinitiation complex or in subsequent initiation and elongation reactions.
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PMID:The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors. 936 58

Human cyclin-dependent kinase (CDK)-activating kinase (CAK) has a dual function in cross-regulation of cell cycle and differentiation, whereas menage a trois 1 (MAT1) assembles CAK and determines CAK's substrate specificity. Although the dynamic state of MAT1 protein levels is found to modulate CAK activity, how intracellular regulation of MAT1 controls CAK activity is unknown. Recent studies demonstrate that retinoic acid (RA)-induced human HL60 cell proliferation/differentiation (P/D) transition is accompanied by MAT1 degradation and decreased CAK phosphorylation of retinoic acid receptor alpha (RARa). Thus, we investigated the biochemical pathway of MAT1 degradation and its relationship with CAK phosphorylation of RARa. We find that RA induces ubiquitination-proteolysis of MAT1 and that ubiquitin-proteasome targets CAK-free MAT1 only. RA-induced MAT1 ubiquitination reduces CAK abundance and decreases CAK phosphorylation of RARalpha, whereas inhibition of MAT1 ubiquitination resists this RA-effect. These findings reveal that RA induces MAT1 ubiquitination to decrease CAK phosphorylation of RARalpha, suggesting a novel mechanism of RA-mediated P/D transition in which MAT1 ubiquitination may act as an integral part of RA-effect to decrease CAK activity in the switch from proliferation to differentiation.
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PMID:Retinoid-modulated MAT1 ubiquitination and CAK activity. 1534 85

Lymphoma is one of the most common malignancies in dogs. Canine lymphoma is similar to human non-Hodgkin's lymphoma (NHL) with shared clinical presentation and histopathological features. This study reports the construction of a comprehensive gene regulatory network (GRN) for canine diffuse large B-cell lymphoma (DLBCL), the most common type of canine lymphoma, and performs analysis for detection of major functional modules and hub genes (the most important genes in a GRN). The canine DLBCL GRN was reconstructed from gene expression data (NCBI GEO dataset: GSE30881) using the STRING and MiMI interaction databases. Reconstructed GRNs were then assessed, using various bioinformatics programmes, in order to analyze network topology and identify major pathways and hub genes. The resultant network from both interaction databases had a logically scale-free pattern. Gene ontology (GO) analysis revealed cell activation, cell cycle phase, immune effector process, immune system development, immune system process, integrin-mediated signalling pathway, intracellular protein kinase cascade, intracellular signal transduction, leucocyte activation and differentiation, lymphocyte activation and differentiation as major GO terms in the biological processes of the networks. Moreover, bioinformatics analysis showed E2F1, E2F4, PTEN, CDKN1A, PCNA, DKC1, MNAT1, NDUFB4, ATP5J, PRKDC, BRCA1, MYCN, RFC4 and POLA1 as the most important hub genes. The phosphatidyl inositol signalling system, P53 signalling pathway, Rac CycD pathway, G1/S checkpoint, chemokine signalling pathway and telomere maintenance were the main signalling pathways in which the protein products of the hub genes are involved.
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PMID:Reconstruction of canine diffuse large B-cell lymphoma gene regulatory network: detection of functional modules and hub genes. 2567 21

The human CDK-activating kinase (CAK), a complex composed of cyclin-dependent kinase (CDK) 7, cyclin H, and MAT1, is a critical regulator of transcription initiation and the cell cycle. It acts by phosphorylating the C-terminal heptapeptide repeat domain of the RNA polymerase II (Pol II) subunit RPB1, which is an important regulatory event in transcription initiation by Pol II, and it phosphorylates the regulatory T-loop of CDKs that control cell cycle progression. Here, we have determined the three-dimensional (3D) structure of the catalytic module of human CAK, revealing the structural basis of its assembly and providing insight into CDK7 activation in this context. The unique third component of the complex, MAT1, substantially extends the interaction interface between CDK7 and cyclin H, explaining its role as a CAK assembly factor, and it forms interactions with the CDK7 T-loop, which may contribute to enhancing CAK activity. We have also determined the structure of the CAK in complex with the covalently bound inhibitor THZ1 in order to provide insight into the binding of inhibitors at the CDK7 active site and to aid in the rational design of therapeutic compounds.
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PMID:The cryoelectron microscopy structure of the human CDK-activating kinase. 3285 1