P300/CBP

protein
Name=E1A binding protein p300
caption=


width=
HGNCid=3373
Symbol=EP300
AltSymbols= (p300)
EntrezGene=2033
OMIM=602700
RefSeq=NM_001429
UniProt=Q09472
PDB=
ECnumber= 2.3.1.48
Chromosome=22
Arm=q
Band=13.2
LocusSupplementaryData=protein
Name=CREB binding protein (Rubinstein-Taybi syndrome)
caption=


width=
HGNCid=2348
Symbol=CREBBP
AltSymbols= (CBP, RSTS)
EntrezGene=1387
OMIM=600140
RefSeq=NM_004380
UniProt=Q92793
PDB=
ECnumber= 2.3.1.48
Chromosome=16
Arm=p
Band=13.3
LocusSupplementaryData=

p300 (also EP300 or E1A binding protein p300) and CBP (also CREBBP or CREB binding protein) are two closely related transcriptional co-activating proteins (or coactivators). p300 and CBP interact with numerous transcription factors and act to increase the expression of their target genes.cite journal | author = Kasper LH, Fukuyama T, Biesen MA, Boussouar F, Tong C, de Pauw A, Murray PJ, van Deursen JM, Brindle PK | title = Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development | journal = Mol. Cell. Biol. | volume = 26 | issue = 3 | pages = 789–809 | year = 2006 | pmid = 16428436 | doi = 10.1128/MCB.26.3.789-809.2006 | issn = ] cite journal | author = Vo N, Goodman RH | title = CREB-binding protein and p300 in transcriptional regulation | journal = J. Biol. Chem. | volume = 276 | issue = 17 | pages = 13505–8 | year = 2001 | pmid = 11279224 | doi = 10.1074/jbc.R000025200 | issn = ]

Protein structure

p300 and CBP have similar structures. Both contain five protein interaction domains: the nuclear receptor interaction domain (RID), the CREB and MYB interaction domain (KIX), the cysteine/histidine regions (CH1 and CH3) and the interferon response binding domain (IBiD). In addition p300 and CBP each contain a protein or histone acetyltransferase (PAT/HAT) domain and a bromodomain that binds acetylated lysines and a PHD finger motif with unknown function.cite journal | author = Spiegelman BM, Heinrich R | title = Biological control through regulated transcriptional coactivators | journal = Cell | volume = 119 | issue = 2 | pages = 157–67 | year = 2004 | pmid = 15479634 | doi = 10.1016/j.cell.2004.09.037 | issn = ]

Conserved domains

p300 and CBP share several conserved domains.

Impact on gene expression

p300 and CBP are thought to increase gene expression in three ways:

* 1) by relaxing the chromatin structure at the gene promoter through their intrinsic histone acetyltransferase (HAT) activity.
* 2) recruiting the basal transcriptional machinery including RNA polymerase II to the promoter.
* 3) acting as adaptor molecules.cite journal | author = Goodman RH, Smolik S | title = CBP/p300 in cell growth, transformation, and development | journal = Genes Dev. | volume = 14 | issue = 13 | pages = 1553–77 | year = 2000 | pmid = 10887150 | doi = 10.1101/gad.14.13.1553 | issn = ]

Function in G protein signaling

An example of a process involving p300 and CBP is G protein signaling. Some G proteins stimulate adenylate cyclase that results in elevation of cAMP. cAMP stimulates PKA, which consists of four subunits, two regulatory and two catalytic. Binding of cAMP to the regulatory subunits causes release of the catalytic subunits. These subunits can then enter the nucleus to interact with transcriptional factors, thus affecting gene transcription. The transcription factor CREB, which interacts with a DNA sequence called a cAMP response element (or CRE), is phosphorylated by PKA on a serine in the KID domain. This modification promotes the interaction of the KID domain of CREB with the KIX domain of CBP or p300 and enhances transcription of CREB target genes, including genes that aid gluconeogenesis. This pathway is initiated by adrenaline binding to the cell of interest.cite journal | author = Mayr B, Montminy M | title = Transcriptional regulation by the phosphorylation-dependent factor CREB | journal = Nat. Rev. Mol. Cell Biol. | volume = 2 | issue = 8 | pages = 599–609 | year = 2001 | pmid = 11483993 | doi = 10.1038/35085068 | issn = ]

Clinical significance

Mutations in CBP, and to a lesser extent p300, are associated with Rubinstein-Taybi Syndrome, which is characterized by severe mental retardation. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of CBP or p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the CBP or p300 protein, while others prevent one copy of the gene from making any protein at all. Although researchers do not know how a reduction in the amount of CBP or p300 protein leads to the specific features of Rubinstein-Taybi syndrome, it is clear that the loss of one copy of the CBP or p300 gene disrupts normal development. Defects in CBP HAT activity appears to cause problems in long-term memory formation.cite journal | author = Korzus E, Rosenfeld MG, Mayford M | title = CBP histone acetyltransferase activity is a critical component of memory consolidation | journal = Neuron | volume = 42 | issue = 6 | pages = 961–72 | year = 2004 | pmid = 15207240 | doi = 10.1016/j.neuron.2004.06.002 | issn = ] CBP and p300 have also been found to be involved in multiple rare chromosomal translocations that are associated with acute myeloid leukemia. For example, researchers have found a translocation between chromosomes 8 and 22 (in the region containing the p300 gene) in several people with a cancer of blood cells called acute myeloid leukemia (AML). Another translocation, involving chromosomes 11 and 22, has been found in a small number of people who have undergone cancer treatment. This chromosomal change is associated with the development of AML following chemotherapy for other forms of cancer. Mutations in the p300 gene have been identified in several other types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Somatic mutations in the p300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast and pancreas. Studies suggest that p300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, p300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form.

Mouse models

CBP and p300 are critical for normal embryonic development, as mice completely lacking either CBP or p300 protein, die at an early embryonic stage.cite journal | author = Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, Newsome D, Bronson RT, Li E, Livingston DM, Eckner R | title = Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300 | journal = Cell | volume = 93 | issue = 3 | pages = 361–72 | year = 1998 | pmid = 9590171 | doi = 10.1016/S0092-8674(00)81165-4 | issn = ] cite journal | author = Tanaka Y, Naruse I, Hongo T, Xu M, Nakahata T, Maekawa T, Ishii S | title = Extensive brain hemorrhage and embryonic lethality in a mouse null mutant of CREB-binding protein | journal = Mech. Dev. | volume = 95 | issue = 1-2 | pages = 133–45 | year = 2000 | pmid = 10906457 | doi = 10.1016/S0925-4773(00)00360-9 | issn = ] In addition, mice which lack one functional copy (allele) of both the CBP and p300 genes (i.e. are heterozygous for both CBP and p300) and thus have half of the normal amount of both CBP and p300, also die early in embryogenesis.cite journal | author = Yao TP, Oh SP, Fuchs M, Zhou ND, Ch'ng LE, Newsome D, Bronson RT, Li E, Livingston DM, Eckner R | title = Gene dosage-dependent embryonic development and proliferation defects in mice lacking the transcriptional integrator p300 | journal = Cell | volume = 93 | issue = 3 | pages = 361–72 | year = 1998 | pmid = 9590171 | doi = 10.1016/S0092-8674(00)81165-4 | issn = ] This indicates that the total amount of CBP and p300 protein is critical for embryo development. Interestingly, data suggest that some cell types can tolerate loss of CBP or p300 better than the whole organism can. Mouse B cells or T cells lacking either CBP and p300 protein develop fairly normally, but B or T cells that lack both CBP and p300 fail to develop "in vivo".cite journal | author = Kasper LH, Fukuyama T, Biesen MA, Boussouar F, Tong C, de Pauw A, Murray PJ, van Deursen JM, Brindle PK | title = Conditional knockout mice reveal distinct functions for the global transcriptional coactivators CBP and p300 in T-cell development | journal = Mol. Cell. Biol. | volume = 26 | issue = 3 | pages = 789–809 | year = 2006 | pmid = 16428436 | doi = 10.1128/MCB.26.3.789-809.2006 | issn = ] cite journal | author = Xu W, Fukuyama T, Ney PA, Wang D, Rehg J, Boyd K, van Deursen JM, Brindle PK | title = Global transcriptional coactivators CREB-binding protein and p300 are highly essential collectively but not individually in peripheral B cells | journal = Blood | volume = 107 | issue = 11 | pages = 4407–16 | year = 2006 | pmid = 16424387 | doi = 10.1182/blood-2005-08-3263 | issn = ] Together, the data indicates that while individual cell types require different amounts of CBP and p300 to develop or survive and that some cell types are more tolerant of loss of CBP or p300 than the whole organism; it appears that many, if not all cell types may require at least some p300 or CBP to develop.

References

External links

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