The integrity of epithelial tissues hinges on the proper distribution of proteins from top to bottom. Loss of this apicobasal polarization is an avenue to various diseases, including inflammation and cancer. Mirka Uhlirova and her team at the Cluster of Excellence for Aging Research CECAD used the fruit fly model to demonstrate how breakdown of epithelial polarity induces Atf3. They show that while ATF3 is essential for Drosophila to live, its chronic activation drives several hallmarks of compromised apicobasal polarity. In contrast, loss of ATF3 restores polarized cellular architecture.
Stress and response
Our cells are constantly exposed to various stimuli which requires balanced responses to maintain their function. Stress-responsive transcription factors are crucial in distilling all these inputs into gene-expression programs to maintain homeostasis. This control, however, must be coordinated not only on the level of single cells, but also on the level of tissues. Loss of polarity represents a significant stress for the cell and a potential risk for the whole organism, as it is critical step towards malignant tissue transformations. Two possible mechanisms are available to avoid severe consequences, as Mirka Uhlirova explains: “Either the cell needs to be eliminated or the polarity must be restored.”
ATF3, a protein of many talents
ATF3 has been defined as a stress response transcription factor, the levels of which increase when cells are challenged with various insults. While best known for its role in in coordinating immune responses, Colin Donohoe, Gábor Csordas and co-workers now highlight ATF3 function in the maintenance of epithelial integrity. In their recent paper, they show how loss of the apicobasal polarity induces ATF3, which in turn alters the cell architecture, prevents differentiation and causes the extrusion of these polarity compromised cells. Strikingly, loss of ATF3 counteracts cell shape changes and extrusion allowing formation of functional adult organs. Combining genome-wide approaches and genetics, the authors provide evidence that ATF3 controls the mechanical properties of the cell, including the cytoskeleton and the nucleoskeleton.
These new findings from the Uhlirova lab shed light on the transcriptional response downstream of polarity loss, a topic which still harbors many open questions. As this regulatory layer is paramount for cancer formation and malignancy, elucidating factors like ATF3 and uncovering their function are important for the better understanding of how these diseases arise and how we can efficiently counter them.
Atf3 links loss of epithelial polarity to defects in cell differentiation and cytoarchitecture
Colin D. Donohoe, Gábor Csordás, Andreia Correia, Marek Jindra, Corinna Klein, Bianca Habermann, Mirka Uhlirova
PLoS Genet 14(3): e1007241.
Prof. Mirka Uhlirova, Ph.D.
phone: +49-221 / 478-84334