P300 and CBP are two closely related proteins that play extensive roles in the body. These proteins are found in nearly all cells and are involved in fundamental cellular activities. Scientists often refer to them as central players due to their broad influence on how cells function and respond to their environment. Understanding their mechanisms helps shed light on many biological processes.
The Role of P300 and CBP
P300 (E1A binding protein p300) and CBP (CREB binding protein) are proteins that act as transcriptional coactivators. This means they assist in turning genes “on,” enabling the cell to read and use the information stored in DNA. They are present throughout the body and participate in a wide array of basic cellular processes. These processes include cell growth, the specialization of cells into different types (differentiation), and how cells manage energy (metabolism).
How P300 and CBP Regulate Genes
P300 and CBP primarily regulate genes through their histone acetyltransferase (HAT) activity. This process involves adding an acetyl group to specific proteins called histones, which act as spools around which DNA is wound. When histones are acetylated, the DNA loosens its grip, becoming more accessible to the cellular machinery responsible for transcribing genes. This increased accessibility allows genes to be expressed, or “read,” by the cell.
Beyond their HAT activity, P300 and CBP also serve as scaffolding proteins. They can physically bring together various other proteins involved in gene regulation, forming complexes that facilitate gene activation. This scaffolding function ensures that all the necessary components are in the right place at the right time for efficient gene transcription. By acting as both an enzyme and a connector, P300 and CBP orchestrate the precise control of gene expression.
P300/CBP in Health and Disease
The proper functioning of P300 and CBP is linked to overall human health, and their dysfunction can contribute to various diseases. Mutations in the gene encoding CBP, for instance, are associated with Rubinstein-Taybi Syndrome, a developmental disorder characterized by intellectual disability, distinctive facial features, and broad thumbs and toes.
In the context of cancer, P300 and CBP can play complex roles, sometimes acting as tumor suppressors and other times contributing to tumor development depending on the specific cellular context. For example, their dysregulation can lead to improper gene expression, disrupting normal cellular pathways that control cell growth and division. Research also suggests their involvement in neurodegenerative diseases, where altered activity could contribute to neuronal damage and decline.
Therapeutic Approaches Targeting P300/CBP
Given their broad involvement in disease, P300 and CBP have become targets for therapeutic interventions. Researchers are exploring ways to modulate their activity, for example, by developing inhibitors or activators of their HAT activity. One such approach involves a British biotech company developing an oral P300/CBP inhibitor currently in a Phase 2a study for relapsed or refractory multiple myeloma. A new treatment, TT125-802, also works by blocking CBP/p300, targeting proteins involved in cancer development.
Targeting these proteins presents challenges due to their widespread roles in the body, which could lead to unintended side effects. However, the development of selective degraders for either CBP or EP300 (p300) is allowing scientists to differentiate their individual roles in various signaling pathways, such as in prostate cancer where EP300 degradation specifically downregulates AR signaling genes. This targeted approach aims to maximize therapeutic benefits while minimizing adverse effects.