P300-CBP coactivator family

P300-CBP coactivator family refers to a group of closely related proteins that play a crucial role in the regulation of gene expression through their intrinsic histone acetyltransferase (HAT) activity. These proteins are essential for the transcriptional activation of genes involved in a wide range of cellular processes, including cell growth, differentiation, and response to external signals. The family primarily consists of two members: p300 (also known as EP300 or E1A-associated protein p300) and CBP (CREB-binding protein). Despite their structural and functional similarities, p300 and CBP are encoded by separate genes and have distinct roles in cellular physiology and pathology, including their involvement in cancer and neurodegenerative diseases.

Function

The P300-CBP coactivator family functions as transcriptional coactivators, interacting with numerous transcription factors to enhance their ability to activate gene expression. Their HAT activity allows them to acetylate lysine residues on histone tails, leading to an open chromatin structure that is more accessible to the transcriptional machinery. This acetylation activity is not limited to histones; p300 and CBP can also acetylate non-histone proteins, thereby modulating their function, stability, and interactions. Through these mechanisms, the P300-CBP coactivator family plays a pivotal role in the regulation of genes critical for cell cycle progression, apoptosis, and response to DNA damage.

Structure

Both p300 and CBP are large proteins, each consisting of several domains that mediate their interactions with other proteins and their enzymatic activity. These include the CH1 (TAZ1), CH2 (TAZ2), CH3 (KIX), bromodomain, and HAT domain, among others. The HAT domain is responsible for their acetyltransferase activity, while the other domains facilitate interactions with a wide array of transcription factors and other regulatory proteins.

Clinical Significance

Mutations and alterations in the expression of p300 and CBP have been implicated in various human diseases. In cancer, mutations that inactivate the HAT activity of p300 and CBP can lead to decreased expression of tumor suppressor genes and contribute to tumor progression. Conversely, aberrant acetylation due to overexpression or mutation of these coactivators can also promote oncogenesis. In addition to cancer, mutations in the genes encoding p300 and CBP are associated with Rubinstein-Taybi syndrome, a developmental disorder characterized by intellectual disability, growth retardation, and distinctive facial features.

Research and Therapeutic Potential

Given their central role in gene regulation, the P300-CBP coactivator family has been a target for therapeutic intervention in various diseases. Small molecule inhibitors and activators of their HAT activity are being explored for the treatment of cancer and neurodegenerative diseases. Understanding the precise mechanisms by which p300 and CBP regulate gene expression and their involvement in disease pathogenesis remains an active area of research, with the potential to uncover novel therapeutic targets.