p300 regulates transcription by directly binding to transcription factors. This interaction is managed by one or more of the p300 domains: the nuclear receptor interaction domain, the CREB and MYB interaction domain, the cysteine/histidine regions and the interferon response binding domain. 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. Enhancer regions, which regulate gene transcription, are known to be bound by p300 and CBP, and ChIP-seq for these proteins has been used to predict enhancers. Work done by Heintzman and colleagues showed that 70% of the p300 binding occurs in open chromatin regions as seen by the association with DNase I hypersensitive sites. Furthermore, they have described that most p300 binding occurs far away from transcription start sites and these binding sites are also associated with enhancer regions as seen by H3K4me1 enrichment. They have also found some correlation between p300 and RNAPII binding at enhancers, which can be explained by the physical interaction with promoters or by enhancer RNAs.
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, is phosphorylated on a serine in the KID domain. This modification is PKA mediated, and 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 can be initiated by adrenaline activating β-adrenergic receptors on the cell surface.
Clinical significance
Mutations in CBP, and to a lesser extent p300, are the cause of 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. 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 several people with a cancer of blood cells called acute myeloid leukemia. 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. In addition, mice which lack one functional copy of both the CBP and p300 genes and thus have half of the normal amount of both CBP and p300, also die early in embryogenesis. This indicates that the total amount of CBP and p300 protein is critical for embryo development. 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. Together, the data indicate that, while individual cell types require different amounts of CBP and p300 to develop or survive and 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.
