Activating Transcription Factor 2, or ATF2, is a protein found within human cells. Encoded by the ATF2 gene on chromosome 2q31.1, ATF2 acts as a master switch, helping to control which genes are turned on or off at any given time. This regulation is fundamental to how cells function and adapt. The protein is composed of 505 amino acids and has a molecular mass of approximately 55 kilodaltons. Understanding ATF2 provides insight into how cells manage their internal processes and respond to their environment.
ATF2’s Core Function in Cells
ATF2 primarily operates as a transcription factor, a type of protein that binds to specific DNA sequences to regulate gene expression. When ATF2 binds to DNA, it can activate or suppress the transcription of nearby genes, influencing whether genetic instructions are converted into proteins. This process controls the production of various proteins needed for cellular activities.
ATF2 can function as a homodimer, meaning it pairs with another ATF2 molecule, or as a heterodimer, by pairing with other proteins like c-Jun. These pairings allow ATF2 to bind to specific DNA sequences, such as the cAMP-responsive element (CRE) or AP-1 consensus sequences, influencing a wide array of cellular processes. Beyond its direct DNA binding, ATF2 also has histone acetyltransferase (HAT) activity, which allows it to acetylate histones H2B and H4, potentially modifying chromatin structure and further impacting gene expression.
ATF2’s Role in Cellular Stress and Growth
ATF2 plays a role in how cells respond to stress and manage their growth and division. When cells encounter challenges like DNA damage or oxidative stress, ATF2 is activated to coordinate a protective response. For example, in response to ionizing radiation, ATF2 is phosphorylated by ATM, which stabilizes its location at sites of DNA double-strand breaks and aids in recruiting DNA repair complexes. This action maintains genomic integrity.
ATF2 also influences the cell cycle, which is the process by which cells grow and divide. It can induce the transcription of cell cycle inhibitors like p21WAF1, which can lead to G2/M cell cycle arrest, a mechanism that pauses cell division for repair or to prevent proliferation of damaged cells. This function can inhibit programmed cell death, or apoptosis, in certain contexts, demonstrating a protective role in some stress responses. Its dual involvement in promoting cell cycle arrest and sometimes inhibiting apoptosis highlights its complex role in cellular coping mechanisms.
ATF2 in Human Diseases
Dysregulation of ATF2, whether increased, decreased, or abnormal, has been linked to various human diseases. In cancer, ATF2 can exhibit a dual role, acting as either a tumor promoter or a tumor suppressor depending on the cancer type and cellular context. For instance, increased ATF2 expression is associated with a poor prognosis in gastric cancer, where it can inhibit sorafenib-induced ferroptosis, a type of cell death. Conversely, in colorectal cancer, low ATF2 levels correlate with worse prognosis and increased tumor invasiveness, suggesting a tumor-suppressive role in this context.
ATF2’s involvement extends to neurodegenerative disorders. In diseases like Alzheimer’s, Parkinson’s, and Huntington’s, ATF2 expression is often downregulated in specific brain regions such as the hippocampus, substantia nigra pars compacta, and caudate nucleus. This suggests compromised neuronal viability in these susceptible areas. However, an increase in ATF2 expression has also been observed in the subependymal layer of Huntington’s disease cases, a region known for increased proliferating progenitor cells, indicating a complex role in neurogenesis within the diseased brain.
ATF2 is also implicated in metabolic conditions. Studies in Drosophila have shown that paternal restraint stress can affect offspring metabolism through ATF2-dependent epigenetic changes, influencing genes involved in amino acid metabolism, glycolysis, and the tricarboxylic acid cycle. In mammalian systems, ATF2 activates the transcription of the phosphoenolpyruvate carboxykinase-cytosolic (PEPCK-C) gene, a key enzyme in hepatic gluconeogenesis, linking ATF2 to glucose metabolism. These associations highlight the broad impact of ATF2 dysregulation across different disease states.
Therapeutic Potential of ATF2
Given its extensive involvement in cellular processes and disease, ATF2 is a significant target for scientific research and drug development. Understanding the precise mechanisms by which ATF2 contributes to various pathologies could lead to new therapeutic strategies. For example, in gastric cancer, silencing ATF2 inhibits malignant cell phenotypes and enhances sensitivity to sorafenib, an anti-cancer drug, by promoting ferroptosis. This suggests modulating ATF2 activity could improve existing treatments.
Targeting ATF2 presents both challenges and promise in precision medicine. Its context-dependent roles, acting as either an oncogene or a tumor suppressor, require careful consideration to develop specific and effective therapies for different disease states. Researchers are exploring how to leverage ATF2’s regulatory functions to design molecules that can specifically activate or inhibit its activity in diseased cells without widespread side effects. This approach could lead to more tailored treatments that directly address the underlying molecular causes of disease.