- Mini review
- Open Access
Latent viruses can cause disease by disrupting the competition for the limiting factor p300/CBP
© The Author(s) 2018
- Received: 7 August 2018
- Accepted: 7 November 2018
- Published: 26 November 2018
CBP and p300 are histone acetyltransferase coactivators that control the transcription of numerous genes in humans, viruses, and other organisms. Although two separate genes encode CBP and p300, they share a 61% sequence identity, and they are often mentioned together as p300/CBP. Zhou et al. showed that under hypoxic conditions, HIF1α and the tumor suppressor p53 compete for binding to the limiting p300/CBP coactivator. Jethanandani & Kramer showed that δEF1 and MYOD genes compete for the limited amount of p300/CBP in the cell. Bhattacharyya et al. showed that the limiting availability of p300/CBP in the cell serves as a checkpoint for HIF1α activity. Here, we use the microcompetition model to explain how latent viruses with a specific viral cis-regulatory element in their promoter/enhancer can disrupt this competition, causing diseases such as cancer, diabetes, atherosclerosis, and obesity.
- HIF1α, p53, CBP
- Transcription factor
With at least 315 different cellular and viral interacting proteins, CBP and p300 are considered the most heavily connected coactivators in the mammalian protein–protein interaction network [1, 2]. Both are histone acetyltransferases, and they control the transcription of numerous genes in humans, viruses, and other organisms. Although two separate genes encode CBP and p300, they share a 61% sequence identity, and they are often mentioned together as p300/CBP .
p300/CBP is a 300-kDa protein that has a CH2 domain, which contains its acetyltransferase activity, and five protein-binding domains . Many studies have shown that competition for the limiting p300/CBP is an important mechanism that regulates transcription and cellular activities. This commentary discusses three of these studies [4–6] and connects their observations to the microcompetition model [7, 8].
Using differential equations and a dimensionless state variable, Zhou et al.  determined the effect of p300 on the steady-state concentrations of proteins. They discovered that under hypoxic conditions, HIF1α and the tumor suppressor p53 compete for binding to the coactivator p300. They showed that p300 is required for full transcriptional activity of both p53 and HIF1α. According to Zhou et al., this competition indicates that p300 is limiting.
The α7 integrin is involved in the differentiation of myoblasts and is negatively regulated by δEF1, a zinc finger transcription factor, and positively regulated by MYOD. δEF1 has an NR (negative region) domain that binds the p300/CBP coactivator. Overexpression of δEF1 inhibits muscle cell differentiation and represses the activation of the muscle creatine kinase enhancer. On the other hand, MYOD activates muscle genes by binding p300, and uses p300/CBP histone acetylase activity to allow for transcription .
Jethanandani & Kramer  transfected C2C12 cells with the p400 fragment of the α7 integrin promoter. Then, they co-transfected the cells with either δEF1 alone, δEF1 and MYOD, or δEF1 and CBP, and measured the CAT reporter activity. They observed that CBP increased CAT activity, i.e., an increase in CBP levels mitigated the repression of α7 by δEF1. Based on their results, Jethanandani & Kramer concluded that p300/CBP is limiting, and that δEF1 competes with MYOD for the limited amounts of p300/CBP in the cell.
Bhattacharyya et al.  infected human gastric epithelium cells with Helicobacter pylori. The results showed an increase in transcription complex formation at the HREs (hypoxia-response elements) of the mcl1 promoter. Then, they observed that the complex included p300, HIF1α, and APE1 (apurinic/apyrimidinic endonuclease 1). Western blotting on whole cell lysates from AGS cells showed that the binding of p300 to the hif1α promoter decreased at higher levels of H. pylori infection, without a decrease in the p300 concentration. Moreover, they found that higher levels of H. pylori infection increased the expression of hif1α, but decreased the expression of the mcl1 promoter, which is transactivated by HIFα. They discovered that at higher H. pylori levels, HIF1α binds to the HIF-binding site (HBS) on the hif1α promoter. Since the HBS is transcriptionally inactive (it lacks the required HIF ancillary sequence, denoted as HAS), this binding does not further transactivate the hif1α promoter. However, this binding has a sequestering effect that limits the intracellular availability of the HIF1α•p300 complex to the mcl1 gene, which decreases mcl1 expression.
The observations in the Bhattacharyya et al. study indicate that p300 is limiting, meaning the HIF1α•p300 complex is limiting. They also show that the decrease in HIF1α•p300 binding to the mcl1 promoter, which decreases mcl1 transcription, is due to competition for the limiting HIF1α•p300 by the hif1α promoter itself. Based on their observations, Bhattacharyya et al. concluded that the limiting availability of p300 in the cell is a checkpoint for HIF1α activity.
List of some human genes that bind the GABP•p300/CBP transcription complex
β2 leukocyte integrin (CD18)
Rosmarin et al. 1998 
Interleukin 16 (IL-16)
Bannert et al. 1999 
Interleukin 2 (IL-2)
Avots et al. 1997 
Interleukin 2 receptor β-chain (IL-2Rβ)
Lin et al. 1993 
IL-2 receptor γ-chain (IL-2 γc)
Markiewicz et al. 1996 
Human secretory interleukin-1 receptor antagonist (secretory IL-1ra)
Smith et al. 1998 
Sowa et al. 1997 
Human thrombopoietin (TPO)
Kamura et al. 1997 
Wang et al. 1993 
Neutrophil elastase (NE)
Folate binding protein (FBP)
Sadasivan et al. 1994 
Cytochrome c oxidase subunit Vb (COXVb)
Cytochrome c oxidase subunit IV
Mitochondrial transcription factor A (mtTFA)
Virbasius et al. 1994 
β subunit of the FoF1 ATP synthase (ATPsynβ)
Villena et al. 1998 
Ouyang et al. 1996 
Oxytocin receptor (OTR)
Hoare et al. 1999 
Our interpretation of the microcompetition model agrees with that of Zuo et al. It is the copy number of the viruses that sequester the limiting GABP•p300/CBP transcription complex and not the ‘infected or not infected’ that determines the fate of the infected individual. Therefore, it should be measured in clinical practice.
“It has been noticed that EBV load in tumor tissues or blood is associated with the clinical progression and prognosis in both lymphoma and NPC. Our result verifies this association. We also emphasize the importance to measure the level of gene expression or copy number in the virus study instead of only concerning ‘with and without’.”
To conclude, the microcompetition model explains how an increase in the copy number of a latent virus that binds the limiting GABP•p300/CBP transcription complex increases the sequestering of the complex. This disrupts the allocation of the complex to cellular genes that compete to bind the complex. When this disruption is large enough, the host develops a disease.
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