BRD4

Bromodomain-containing protein 4 is a is_associated_with::protein that in humans is encoded by the BRD4 is_associated_with::gene.

BRD4 is a member of the BET (bromodomain and extra terminal domain) family, which also includes is_associated_with::BRD2, is_associated_with::BRD3, and is_associated_with::BRDT. BRD4, similar to other BET family members, contains two is_associated_with::bromodomains that recognize is_associated_with::acetylated is_associated_with::lysine residues. BRD4 also has an extended C-terminal domain with little sequence homology to other BET family members.

Structure
The two bromodomains in BRD4, termed BD1 and BD2, consist of 4 is_associated_with::alpha-helices linked by 2 loops. The ET domain structure is made up of 3 alpha-helices and a loop. The C-terminal domain of BRD4 has been implicated in promoting is_associated_with::gene transcription through interaction with the transcription elongation factor is_associated_with::P-TEFb and is_associated_with::RNA polymerase II.

Function
The protein encoded by this gene is homologous to the murine protein MCAP, which associates with chromosomes during mitosis, and to the human RING3 protein, a serine/threonine kinase. Each of these proteins contains two bromodomains, a conserved sequence motif which may be involved in chromatin targeting. This gene has been implicated as the chromosome 19 target of translocation t(15;19)(q13;p13.1), which defines the is_associated_with::NUT midline carcinoma. Two alternatively spliced transcript variants have been described.

Role in cancer
Most cases of is_associated_with::NUT midline carcinoma involve translocation of the BRD4 with NUT genes. BRD4 is often required for expression of is_associated_with::Myc and other "tumor driving" oncogenes in hematologic cancers including is_associated_with::multiple myeloma and is_associated_with::acute myelogenous leukemia. BRD4 is a major target of is_associated_with::BET inhibitors, a class of pharmaceutical drugs currently being evaluated in clinical trials.

Interactions
Notably, BRD4 interacts with is_associated_with::P-TEFb via its P-TEFb interaction domain (PID), thereby stimulating its kinase activity and stimulating its phosphorylation of the carboxy-terminal domain (CTD) of is_associated_with::RNA polymerase II.

BRD4 has been shown to interact with is_associated_with::GATA1, is_associated_with::JMJD6, is_associated_with::RFC2, is_associated_with::RFC3, is_associated_with::RFC1, is_associated_with::RFC4 and is_associated_with::RFC5.

BRD4 has also been implicated in binding with the diacetylated Twist protein, and the disruption of this interaction has been shown to suppress tumorigenesis in basal-like breast cancer.

BRD4 has also been shown to interact with a variety of inhibitors, such as MS417; inhibition of BRD4 with MS417 has been shown to down-regulate NF-kB activity seen in HIV-associated kidney disease. BRD4 also interacts with RVX-208, which is being evaluated for treatment of is_associated_with::atherosclerosis and is_associated_with::cardiovascular disease.