Journal Club: Cancer Biology, Neuroscience, Stem Cell Biology, and Cancer Biology
One of the ways an aberrant cell becomes cancerous is by becoming less adherent to its surrounding cells. Integrins are a class of cell receptors that assist in tissue adhesion, and by changing expression of integrins, a cell can move more freely away from its tissue of origin and metastasize. While it is well known that the dysregulation of integrins contributes to the development of cancer, it is not known exactly how this process occurs. In this paper, researchers identified the method of α5 integrin dysregulation causing metastasis in mammary epithelial cells. They found that MEK signaling activated Myc, which reduced expression of the chromatin remodeler Brahmin. Reduced Brahmin led to increased C/EBPβ, which in turn led to increased α5 integrin expression and improved metastasis.
A common cause of a relapse in behavior (in this case, drinking alcohol after a period of abstinence) is triggering of cue-induced cravings: the memory of an event associated with the behavior induces a desire to repeat the behavior. Recent work has shown that memories are particularly susceptible to rewriting upon remembrance, or “reconsolidation,” which seems to be dependent on protein synthesis via mTORC1. Given how apparently easy it is for us to modify our memories upon recall (considering how unreliable witness accounts can be), an attractive treatment for alcoholism is to modify, inhibit or destroy the behavior-associated memories, and inhibition of mTORC1 is one potential target. In fact, the researchers found that inhibition of mTORC1 either systemically or locally in the amygdala resulted in inhibition of relapse upon exposure to cues.
One remarkable feature of embryonic stem cells, or ES cells, is their ability to suppress tissue-specific genes and retain an undifferentiated phenotype. Through this genetic program, ES cells retain their pleuripotency, or their ability to later differentiate into any cell type. Cells often suppress expression of genes through DNA demethylation, which practically blocks gene transcription from being able to occur. Tet enzymes help to control DNA demethylation and are therefore an attractive target for compounds that might be able to induce pleuripotency in non-ES cells. Interestingly, while similar enzymes require vitamin C as a cofactor for their activity, Tet enzymes are typically incubated in the absence of the vitamin. In this paper, researchers incubated ES cells with vitamin C and saw a remarkable improvement in Tet activity and an increase in DNA demethylation, improving the quality of ES cells.
Mature, antibody-producing B-cells go through multiple checkpoints during their development that ensure that the B-cell is producing a functional antibody. If the partially completed antibody fails to signal properly during its development, the cell dies and the nonfunctional antibody is never synthesized. In this paper, researchers identify the molecular mechanisms that lead the cell to apoptosis (death) upon expression of a nonfunctional antibody. They found that PAX5 activates Bach2, which binds to BCL-6, thereby inhibiting BCL-6’s ability to inhibit p53. With p53 active, the cell begins the process of apoptosis. Leukemia patients with low Bach2 expression tended to have a poorer prognosis of disease, probably because of a lack of apoptosis upon nonfunctional antibody expression.