14-3-3ζ is one of 7 members of the 14-3-3 protein family, which is ubiquitously expressed and highly conserved among plants and mammals. This protein family is known for regulating signal transduction pathways primarily through binding phosphoserine proteins, though it can also bind phosphothreonine proteins and unphosphorylated proteins. By extension, 14-3-3 proteins are involved in a wide range of biological processes, including metabolism, transcription, apoptosis, protein transport, and cell cycle regulation. This combination of dependence on phosphorylation and widespread biological impact results in dynamic regulation of multiple signalling pathways and allows for cellular adaptation to environmental changes.
In particular, 14-3-3ζ is a key player in regulating cell survival and interacts with many apoptotic proteins, including Raf kinases, BAX, BAD, NOXA, and caspase-2. For the most part,14-3-3ζ negatively regulates apoptosis by binding and sequestering BAD and BAX in the cytoplasm, effectively preventing activation of proapoptotic Bcl-2 and Bcl-XL, as well as by preventing NOXA from inhibiting antiapoptotic MCL1. As a result, 14-3-3ζ functions to protect the cell from environmental stresses, such as chemotherapy-induced death, anoikis, growth factor deprivation, and hypoxia. As an example of its dynamic activity, 14-3-3ζ activates autophagy under hypoxic conditions by binding ATG9A, while it prevents autophagy under hyperglycemic conditions by binding Vps34. Furthermore, 14-3-3ζ may regulate glucosereceptor trafficking in response to insulin levels through its interaction with IRS1.
The14-3-3 protein zeta/delta (14-3-3ζ) is a protein (in humans encoded by the YWHAZgene on chromosome 8) with an important apoptotic constituents. During a normal embryologic processes, or during cell injury (such as ischemia-reperfusion injury during heart attacks and strokes) or during developments and processes in cancer, an apoptotic cell undergoes structural changes including cell shrinkage, plasma membrane blebbing, nuclear condensation, and fragmentation of the DNA and nucleus. This is followed by fragmentation into apoptotic bodies that are quickly removed by phagocytes, thereby preventing an inflammatory response. It is a mode of cell death defined by characteristic morphological, biochemical and molecular changes. It was first described as a "shrinkage necrosis", and then this term was replaced by apoptosis to emphasize its role opposite mitosis in tissue kinetics. In later stages of apoptosis the entire cell becomes fragmented, forming a number of plasma membrane-bounded apoptotic bodies which contain nuclear and or cytoplasmic elements. The ultrastructural appearance of necrosis is quite different, the main features being mitochondrial swelling, plasma membrane breakdown and cellular disintegration. Apoptosis occurs in many physiological and pathological processes. It plays an important role during embryonal development as programmed cell death and accompanies a variety of normal involutional processes in which it serves as a mechanism to remove "unwanted" cells.
The human surfactant protein A, an innate immunity molecule (encoded by two genes SFTPA1 and SFTPA2) appears to be binding with the 14-3-3 protein family. Furthermore, inhibition of 14-3-3 was correlated with lower levels of the surfactant protein indicating a relationship between surface and 14-3-3 proteins. Surfactant is an important element in the maintenance of lung and respiratory functions. A lack of surfactant is closely related to respiratory distress syndrome. Pretermneonates who exhibit neonatal respiratory distress syndrome (NRDS) exhibit a deficiency of surfactant. All together, the 14-3-3 protein may have a significant role in respiratory function and NRDS.
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