KLF4 Binds SM22α Promoter Via a G/C Repressor Site (p 685)
Salmon et al uncover a mechanism in smooth muscle cells that controls the switch from quiescence to proliferation.
In walls of blood vessels, smooth muscle cells (SMCs) proliferate only in extreme circumstances. During vessel injury, for example, SMCs increase their numbers to repair the wound, and during atherosclerosis, they contribute to the formation of plaques. Thus, understanding what regulates SMC proliferation could help both with vessel healing and attenuating atherosclerosis. It is known that genes associated with the differentiated SMCs—SMC marker genes—are downregulated when these cells switch from noncycling to a cycling phenotype and that this switch is promoted by the transcription factor KLF4. However, there was no direct evidence that KLF4 actually downregulated the marker genes in question—until now. Salmon et al showed that after vascular injury in mice, KLF4 binds to a sequence element upstream of the marker gene SM22α, recruits other transcription factors, and causes transcriptional suppression. This element—called a G/C repressor—is present in other SMC marker genes, and so the authors suggest that these additional marker genes would be similarly regulated. In addition to examining these genes, it will be interesting to see if KLF4 also controls the proliferation switch that contributes to plaque formation in atherosclerosis.
p120-S879 Phosphorylation and Adherens Junctions (p 739)
A phosphorylation switch that controls blood vessel permeability has potential as an anti-inflammatory target, say Vandenbroucke St Amant et al.
Blood vessel endothelial cells maintain a tight barrier between the blood and surrounding tissues by firmly linking together. These links are made by cadherin molecules from neighboring endothelial cells, as they stick together to form what are known as adherens junctions. Whereas the binding of p120-catenin to cadherins confers stability to adherens junctions, the activity of kinase PKCα and pro-inflammatory mediators, such as thrombin, cause junction instability and dissociation. This loosening of the junctions increases vessel permeability, allowing inflammatory cells to penetrate body tissues. Vandenbroucke St Amant and colleagues investigated whether thrombin and PKCα might somehow target p120-catenin. They found that PKCα phosphorylated p120-catenin at serine-879 in the C-terminal domain of the protein. This phosphorylation event triggered the dissociation of p120 from junctions and increased permeability. Importantly, in mice carrying a version of p120-catenin that could not be phosphorylated at S879, vascular permeability and resulting lung edema were prevented. Pharmaceutically inhibiting this phosphorylation event could be a novel anti-inflammatory strategy, say the team.
Sca-1 Knockout and Progenitor Cells (p 750)
Bailey et al discover why cardiac progenitor cells need the marker Sca-1.
Cardiac progenitor cells present in the mammalian adult heart are thought to contribute, at least in part, to the general maintenance and repair of cardiac tissue. For example, these progenitor cells increase in number after myocardial infarction. Thus, understanding the biology of cardiac progenitor cells could provide important information for regenerative medicine research. Sca-1 is widely accepted as a marker of cardiac progenitors, but surprisingly, little is known about what this protein does. Bailey et al examined mice that lacked functional Sca-1 and found that not only did the mice have enlarged hearts and impaired cardiac function, but their survival after infarction was lower as well. Hearts of the mutant mice also had a lower number of progenitor cells, whereas the existing cells exhibited decreased proliferation rates and evidence of differentiation—the increased expression of cardiomyocyte-specific genes. This tendency toward differentiation was probably caused by increased expression of genes of the Wnt/β-catenin signaling pathway, a pathway known to promote differentiation in a number of cell types. Together, the results highlight the importance of Sca-1 in maintaining progenitor phenotype and function and thereby the overall health of the heart.
- © 2012 American Heart Association, Inc.