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Histone acetyltransferase p300 also known as p300 HAT or E1A-associated protein p300 (where E1A = adenovirus early region 1A) also known as EP300 or p300 is an
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that, in humans, is encoded by the ''EP300''
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. It functions as
histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylation, acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine, ε-''N''-acetyllysine. DNA is wrapped around his ...
that regulates transcription of genes via chromatin remodeling by allowing histone proteins to wrap DNA less tightly. This enzyme plays an essential role in regulating
cell growth Cell most often refers to: * Cell (biology), the functional basic unit of life * Cellphone, a phone connected to a cellular network * Clandestine cell, a penetration-resistant form of a secret or outlawed organization * Electrochemical cell, a de ...
and division, prompting cells to mature and assume specialized functions (differentiate), and preventing the growth of cancerous tumors. The p300 protein appears to be critical for normal development before and after
birth Birth is the act or process of bearing or bringing forth offspring, also referred to in technical contexts as parturition. In mammals, the process is initiated by hormones which cause the muscular walls of the uterus to contract, expelling the f ...
. The EP300 gene is located on the long (q) arm of the human chromosome 22 at position 13.2. This gene encodes the
adenovirus Adenoviruses (members of the family ''Adenoviridae'') are medium-sized (90–100 nm), nonenveloped (without an outer lipid bilayer) viruses with an icosahedral nucleocapsid containing a double-stranded DNA genome. Their name derives from t ...
E1A-associated cellular p300 transcriptional co-activator protein. EP300 is closely related to another gene, CREB binding protein, which is found on human chromosome 16.


Function

p300 HAT functions as
histone acetyltransferase Histone acetyltransferases (HATs) are enzymes that acetylation, acetylate conserved lysine amino acids on histone proteins by transferring an acetyl group from acetyl-CoA to form ε-N-acetyllysine, ε-''N''-acetyllysine. DNA is wrapped around his ...
that regulates transcription via chromatin remodeling, and is important in the processes of cell proliferation and differentiation. It mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. p300 HAT contains a bromodomain which is involved in IL6 signaling. This gene has also been identified as a co-activator of HIF1A (hypoxia-inducible factor 1 alpha), and, thus, plays a role in the stimulation of hypoxia-induced genes such as VEGF.


Mechanism

The p300 protein carries out its function of activating transcription by binding to
transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
s, and the transcription machinery. On the basis of this function, p300 is called a transcriptional coactivator. The p300 interaction with transcription factors is managed by one or more of p300 domains: the nuclear receptor interaction domain (RID), the KIX domain ( CREB and MYB interaction domain), the
cysteine Cysteine (; symbol Cys or C) is a semiessential proteinogenic amino acid with the chemical formula, formula . The thiol side chain in cysteine enables the formation of Disulfide, disulfide bonds, and often participates in enzymatic reactions as ...
/
histidine Histidine (symbol His or H) is an essential amino acid that is used in the biosynthesis of proteins. It contains an Amine, α-amino group (which is in the protonated –NH3+ form under Physiological condition, biological conditions), a carboxylic ...
regions (TAZ1/CH1 and TAZ2/CH3) and the interferon response binding domain (IBiD). The last four domains, KIX, TAZ1, TAZ2 and IBiD of p300, each bind tightly to a sequence spanning both transactivation domains 9aaTADs of transcription factor p53.


Clinical significance

Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in the EP300 gene are responsible for a small percentage of cases of Rubinstein-Taybi syndrome. These mutations result in the loss of one copy of the gene in each cell, which reduces the amount of p300 protein by half. Some mutations lead to the production of a very short, nonfunctional version of the 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 p300 protein leads to the specific features of Rubinstein-Taybi syndrome, it is clear that the loss of one copy of the EP300 gene disrupts normal development. Chromosomal rearrangements involving chromosome 22 have rarely been associated with certain types of
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
. These rearrangements, called translocations, disrupt the region of chromosome 22 that contains the EP300 gene. For example, researchers have found a translocation between chromosomes 8 and 22 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 EP300 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 EP300 gene have been found in a small number of solid tumors, including cancers of the colon and
rectum The rectum (: rectums or recta) is the final straight portion of the large intestine in humans and some other mammals, and the gut in others. Before expulsion through the anus or cloaca, the rectum stores the feces temporarily. The adult ...
,
stomach The stomach is a muscular, hollow organ in the upper gastrointestinal tract of Human, humans and many other animals, including several invertebrates. The Ancient Greek name for the stomach is ''gaster'' which is used as ''gastric'' in medical t ...
,
breast The breasts are two prominences located on the upper ventral region of the torso among humans and other primates. Both sexes develop breasts from the same embryology, embryological tissues. The relative size and development of the breasts is ...
, and
pancreas The pancreas (plural pancreases, or pancreata) is an Organ (anatomy), organ of the Digestion, digestive system and endocrine system of vertebrates. In humans, it is located in the abdominal cavity, abdomen behind the stomach and functions as a ...
. Studies suggest that EP300 mutations may also play a role in the development of some
prostate cancer Prostate cancer is the neoplasm, uncontrolled growth of cells in the prostate, a gland in the male reproductive system below the bladder. Abnormal growth of the prostate tissue is usually detected through Screening (medicine), screening tests, ...
s, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, EP300 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.


Interactions

EP300 has been shown to interact with: * BCL3, * BRCA1, * CDX2, * CEBPB, * CITED1, * CITED2, * DDX5, * DTX1, * EID1, * ELK1, * ESR1, * FEN1, * GPS2, * HIF1A, * HNF1A, * HNRPU, * ING4, *
ING5 Inhibitor of growth protein 5 is a protein that in humans is encoded by the ''ING5'' gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA tha ...
, * IRF2, * LEF1, * MAF, * MAML1, * MEF2C, * MEF2D, * MYBL2, * Mdm2, *
MyoD MyoD, also known as myoblast determination protein 1, is a protein in animals that plays a major role in regulating muscle differentiation. MyoD, which was discovered in the laboratory of Harold M. Weintraub, belongs to a family of proteins kn ...
, * MEF2A, * NCOA6, * NFATC2, * NPAS2, * P53, * PAX6, * PCNA, * PROX1, * PTMA, * PPARA, * PPARG, * RORA, * RELA, *
SMAD1 Mothers against decapentaplegic homolog 1 also known as SMAD family member 1 or SMAD1 is a protein that in humans is encoded by the ''SMAD1'' gene. Nomenclature SMAD1 belongs to the SMAD (protein), SMAD, a family of proteins similar to the gene p ...
, * SMAD2, * SMAD7, * SNIP1, * SS18, * STAT3, * STAT6, * TAL1, * TCF3, * TFAP2A, * TGS1, * TRERF1, * TSG101, * THRA, * TWIST1, * YY1, and * Zif268.


References


Further reading

* * * * *


External links


GeneReviews/NCBI/NIH/UW entry on Rubinstein-Taybi Syndrome

GeneCard
* * * {{DEFAULTSORT:Ep300 Transcription coregulators