STAT mice are genetically engineered mice developed to study Signal Transducers and Activators of Transcription (STAT) proteins. These proteins are important components of cellular communication networks, influencing how cells respond to various signals. Researchers use these mouse models to investigate STAT proteins’ roles in biological processes, providing insights into their function in health and disease.
STAT Proteins: Cellular Messengers
STAT proteins form a family of intracellular transcription factors that act as communicators within cells. There are seven mammalian STAT family members: STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6. These proteins typically reside in the cytoplasm, awaiting signals from outside the cell. When external signals, such as hormones, growth factors, or cytokines, bind to specific receptors on the cell surface, they activate associated enzymes called Janus kinases (JAKs).
JAKs then phosphorylate tyrosine residues on the STAT proteins. This phosphorylation causes STAT proteins to change shape and form pairs, or dimers. These activated STAT dimers then move into the cell’s nucleus, where they bind to DNA sequences in the promoter regions of target genes. By binding to these regions, STAT proteins regulate gene expression. This process allows them to control a wide array of cellular functions, including cell growth, division, differentiation, immune responses, and programmed cell death.
Mouse Models in STAT Research
Mice are widely used as model organisms in biomedical research due to their genetic and physiological similarities to humans. Approximately 95% of protein-coding genes are shared between mice and humans, making mouse studies highly relevant for understanding human biology. Mice also offer practical advantages, such as their small size, relatively short lifespan, rapid reproduction, and ease of maintenance in controlled environments. These characteristics allow researchers to study disease progression over a compressed timeline and to conduct experiments with consistent genetic backgrounds.
“STAT mice” are created through genetic engineering techniques to manipulate specific STAT genes. One common method involves creating “knockout mice,” where a particular STAT gene is inactivated or removed from the mouse’s genome. This is typically achieved by modifying embryonic stem cells and then introducing these modified cells into mouse embryos. The resulting mice, when bred, can lack a functional copy of the targeted STAT gene, allowing researchers to observe the consequences of its absence on biological processes.
Another approach involves generating “transgenic mice,” where extra copies of a STAT gene, or modified versions, are introduced into the mouse’s DNA. This can be done by injecting the desired DNA directly into the nucleus of a fertilized mouse egg. These genetic modifications help scientists understand the functions of different STAT proteins by observing how their altered expression impacts cellular behavior and overall organismal health. Studying these modified mice provides insights into the complex roles of STAT proteins in various biological systems and their contributions to disease development.
STAT Pathways and Human Health
Dysregulation of STAT pathways contributes to numerous human health conditions, including cancers, autoimmune, and infectious diseases. Aberrant activation of STAT3 is observed in many cancers, such as breast, lung, colon, and pancreatic cancers, as well as glioblastomas and multiple myeloma. This activation can promote tumor cell proliferation, survival, and invasion. STAT5 proteins are implicated in leukemias like chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), with elevated activity linked to cancer cell survival and therapy resistance.
STAT pathways also play roles in autoimmune disorders. Gain-of-function mutations in STAT1 can lead to immune dysregulation and increased susceptibility to autoimmune diseases like lupus, type 1 diabetes, and thyroid disease. This overactivity can cause the immune system to mistakenly attack the body’s own tissues. STAT3 and STAT5 activation are also hallmarks of several autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus.
STAT proteins are central to the body’s response to infectious diseases. The JAK-STAT pathway mediates the innate immune response against viral, bacterial, and fungal infections. Defects in STAT proteins can lead to increased susceptibility to pathogens. For example, STAT1 mutations can increase vulnerability to fungal, viral, and bacterial infections. Research using STAT mouse models has been instrumental in understanding these disease mechanisms and identifying potential therapeutic targets, leading to the development of JAK/STAT inhibitors that modulate STAT activity and show promise in treating certain cancers and inflammatory conditions.