Journal Club: Cancer Biology, Cell Biology, and Genetics

CANCER BIOLOGY: Increased hepatocarcinogenesis from GSNOR deficiency in mice is prevented by pharmacological inhibition of iNOS. Tang, C.H.; Wei, W.; Hanes, M.A.; Liu, L. Cancer Research.  February 25. [Epub ahead of print]

Nitric oxide (NO) is a free radical created by our cells with a variety of functions: for example, macrophages release NO to kill pathogens.  NO is made by a number of nitric oxide synthases, or NOSs, and iNOS is a unique synthase that is inducible under conditions of oxidative stress.

When NO is made under oxidative stress, the NO reacts with superoxides to create lethal byproducts, which is how macrophages kill bacteria with NO. GSNOR is another regulator of cellular NO levels and GSNOR-deficient mice have many biological defects, including increased susceptibility to bacterial infection and high levels of liver cancer, which are somehow related to intracellular NO levels.

Here, researchers have tied the function of one NO regulator, GSNOR, to another regulator, iNOS, by showing that defects typical of the GSNOR knockout can be prevented by inhibiting iNOS.

CELL BIOLOGY: Glucose sensor O-GlcNAcylation coordinates with phosphorylation to regulate circadian clock. Kaasik, K. et al. (Fu). Cell Metabolism. 17(2):291-302.

Variations in circadian rhythm are what make some of us early risers, while others tend to stay up and wake later. The circadian “clock” regulates many body systems, including metabolism.  Alterations in circadian rhythm significantly affect multiple measures of metabolic health. In turn, these systems also regulate the circadian clock: For example, diet can influence the circadian clock.

One known circadian regulatory mechanism involves phosphorylation of the signaling mediator glycogen synthase kinase3B (GSK3B).

In this paper, researchers found that a known target of GSK3B also regulates GSK3B through addition of the sugar O-linked N-Acetylglucosamine (O-GlcNac) to the kinase. Modification of these sugars altered circadian rhythm in mice and in fruit flies, and natural circadian rhythm also affected baseline O-GlcNac levels.

CELL BIOLOGY: D-series resolvins attenuate vascular smooth muscle cell activation and neointimal hyperplasia following vascular injury. Miyahara, T. et al. (Conte). FASEB Journal. February 21. [Epub ahead of print]

Contrary to previous belief, current opinion holds that atherosclerosis is a disease of vascular inflammation, and not simply “clogging” of arteries. Many popular treatments of atherosclerosis, such as balloon stenting or vascular grafting, often require replacement because they cannot prevent the inflammatory process that leads to additional vascular complications.

Recently, researchers have identified a class of lipid mediators, including molecules known as “resolvins,” that help attenuate vascular inflammation.

Here, researchers found that administration of D-resolvins attenuated acute vascular injury by downregulating release of inflammatory mediators by vascular smooth muscle cells; furthermore, they found evidence of endogenous production and release of resolvins in response to injury.

GENETICS: Transition of a microRNA from repressing to activating translation depending on the extent of base pairing with the target. Saraiya, A.A.; Li, W.; Wang, C.C. PLoS One. 2013;8(2):e55672.

Just two weeks ago, this column featured a paper that studied the regulation of microRNAs: short RNA molecules that can rapidly down-regulate the expression of particular genes via homology to the mRNA of that gene. Typically, microRNAs are thought of as strictly repressive regulators. However, there have also been recent studies showing microRNA enhancement of gene expression.

In this paper, researchers discovered that a microRNA can change from being repressive of a gene’s expression to enhancing that same gene’s expression just by the extent of base pairing between the microRNA and the gene’s mRNA. When the microRNA was completely complementary, it enhanced expression of the gene, but significantly lost enhancing capacity with each progressive base pair switch away from complementarity.