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Literature summary for 2.7.11.23 extracted from
- BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain (2012), Proc. Natl. Acad. Sci. USA, 109, 6927-6932.
Application
| Application | Comment | Organism |
|---|---|---|
| medicine | the bromodomain protein, BRD4, is a therapeutic target in acute myeloid leukemia, multiple myeloma, Burkitts lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease. Loss of the enzyme BRD4 is a prognostic signature for metastatic breast cancer | Mus musculus |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| recombinant expression of BRD4 in Escherichia coli and in Spodoptera frugiperda Sf9 insect cells, in vitro transcription was done using HeLa nuclear extract and the MHC I gene promoter in the presence of ATP | Mus musculus |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide | i.e. CPI203, phosphorylation of the CTD Ser2 is inhibited in vivo by a BRD4 inhibitor that blocks its binding to chromatin | Mus musculus |  |
| (S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate | i.e. JQ1 | Mus musculus | |
| 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole | - |
Mus musculus | |
| apigenin | - |
Mus musculus | |
| additional information | BRD4 phosphorylation of the CTD is not affected by either flavopiridol or roscovitine. Inhibitors of DNA-PK and MAP (Erk1/2) CTD kinases as well as common broad spectrum kinase inhibitors have no effect on BRD4 | Mus musculus |
KM Value [mM]
| KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.000085 | - |
[DNA-directed RNA polymerase] | recombinant enzyme, pH 6.0-7.5, temperature not specified in the publication | Mus musculus | |
| 0.01 | - |
ATP | recombinant enzyme, pH 6.0-7.5, temperature not specified in the publication | Mus musculus | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| nucleus | - |
Mus musculus | 5634 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | required | Mus musculus | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + [DNA-directed RNA polymerase] | Mus musculus | phosphorylation at Ser2 by BRD4 kinase. BRD4 phosphorylates the Pol II CTD in in vitro transcription reactions | ADP + phospho-[DNA-directed RNA polymerase] | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Mus musculus | Q9ESU6 | - |
- |
Posttranslational Modification
| Posttranslational Modification | Comment | Organism |
|---|---|---|
| phosphoprotein | recombinant BRD4, purified from insect SF9 cells, autophosphorylates, and recombinant BRD4 purified from Escherichia coli also autophosphorylates | Mus musculus |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
| recombinant BRD4 from Escherichia coli and from Spodoptera frugiperda Sf9 insect cells | Mus musculus |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| embryonic fibroblast | - |
Mus musculus | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + [DNA-directed RNA polymerase] | phosphorylation at Ser2 by BRD4 kinase. BRD4 phosphorylates the Pol II CTD in in vitro transcription reactions | Mus musculus | ADP + phospho-[DNA-directed RNA polymerase] | - |
? | |
| ATP + [DNA-directed RNA polymerase] | BRD4 phosphorylates CTD proteins containing the consensus sequence and Ala substitutions at Ser5 and Ser7, but it does not phosphorylate Ser2 substitutions either alone or combined with Ser5. BRD4 phosphorylates all consensus CTD heptad repeats. Assay substrate is recombinant full-length human GST-tagged CTD | Mus musculus | ADP + phospho-[DNA-directed RNA polymerase] | - |
? | |
| additional information | BRD4 autophosphorylation in an in vitro kinase reaction. Phoshorylation site determination with RNA Pol II CTD using a series of GST-CTD fusions with 25- or 16-heptad repeats bearing alanine substitutions in every heptad at Ser2, Ser5, Ser7, or Thr4 as substrates | Mus musculus | ? | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| More | BRD4 domain mapping by mass spectrometry, comparison of kinase subdomain architecture and organization of eukaryotic protein kinases and atypical protein kinases, overview | Mus musculus |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| BRD4 | - |
Mus musculus |
| RNA polymerase II CTD Ser2 kinase | - |
Mus musculus |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 6 | 7.5 | high activity | Mus musculus |
pH Range
| pH Minimum | pH Maximum | Comment | Organism |
|---|---|---|---|
| 6 | 9 | active at | Mus musculus |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Mus musculus | |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.022 | 0.081 | pH 6.0-7.5, temperature not specified in the publication | Mus musculus | (S)-tert-butyl 2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetate | |
| 0.03 | 0.099 | pH 6.0-7.5, temperature not specified in the publication | Mus musculus | (S)-2-(4-(4-chlorophenyl)-2,3,9-trimethyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)acetamide | |
General Information
| General Information | Comment | Organism |
|---|---|---|
| malfunction | loss of the enzyme BRD4 is associated with metastatic breast cancer. BRD4 knockdown suppresses global transcription in murine embryonic fibroblasts, overview | Mus musculus |
| physiological function | the bromodomain protein BRD4 is an atypical kinase that phosphorylates serine 2 of the RNA polymerase II C-terminal domain directly both in vitro and in vivo under conditions where other CTD kinases are inactive. It is involved in acute myeloid leukemia, multiple myeloma, Burkitt's lymphoma, NUT midline carcinoma, colon cancer, and inflammatory disease. BRD4 also contributes to regulation of both cell cycle and transcription of oncogenes, HIV, and human papilloma virus. It is a regulator of eukaryotic transcription | Mus musculus |
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