CREBBP and Associated Diseases
Creative Biolabs is committed to accelerating the development of gene therapy. Based on our understanding of gene therapy and potential target genes, we now describe the CREBBP gene and associated diseases for our clients all over the world.
Overview of CREBBP
Cyclic adenosine monophosphate response element binding protein, also known as CREB-binding protein, CREBBP, CBP, or KAT3A, is a coactivator encoded by the CREBBP gene. CBP has unique acetyltransferase activity and is known to be associated with more than 16,000 genes and a variety of pathophysiologies in humans.
Fig.1 p300/CREB-binding protein (CBP) regulates the cell cycle at multiple points. (Attar, 2017)
Functions of CREBBP
Together with EP300 (p300), CBP is a homologous lysine acetyltransferase with multiple cellular functions. They can act as a scaffold linking sequence-specific DNA-binding factors and basal transcription machinery to regulate transcription and facilitate transcription through the acetylation of histones, transcription factors, and autoacetylation. A variety of different transcription factors can regulate the expression of thousands of genes in almost all cell types through p300/CBP. p300 and CBP can also regulate multiple fundamental biological processes including proliferation, cell cycle, cell differentiation, and DNA damage response. Cell-based model experiments demonstrate a direct role of CBP in promoting cell cycle progression. From the origin firing to the synthesized DNA, p300/CBP plays an important regulatory role in the entire process of DNA replication.
Fig.2 Frequency of the different types of mutations in p300 and CBP in cancer. (Attar, 2017)
P300 and CBP in Cancer
As a classic tumor suppressor, p300/CBP can exert tumor suppressor effects by promoting the function of other tumor suppressors such as p53, RB1, and BRCA1 or by inducing transforming growth factor-beta (TGF-β) responsive genes. p300/CBP is involved in p53-mediated functions and promotes nuclear accumulation and stability of p53.
Studies have shown that loss of heterozygosity (LOH) frequencies at 1% to 50% of the p300 or CBP locus can be detected in a variety of cancers, including colorectal, gastric, ovarian, and hepatocellular carcinomas. Numerous next-generation sequencing results showed mutations of p300/CBP in cancer are mostly missense point mutations, with a higher frequency in the lysine acetyltransferase (KAT) domain. For example, mutations at Y1450 and Y1503 in the KAT domain of CBP, which reduce or eliminate KAT activity, are among the most common mutations in cancer. In conclusion, further research on p300/CBP is beneficial to deeply understand the pathogenesis of cancer and develop therapeutic options.
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Reference
- Attar, N.; Kurdistani, S.K. Exploitation of EP300 and CREBBP lysine acetyltransferases by cancer. Cold Spring Harbor perspectives in medicine. 2017, 7(3): a026534.
