Reviews & Analysis

The ACE enzyme, a target of blood pressure medications, now gains a new function in mice. The enzyme cleaves proteins linked to the cell membrane by GPI linkages, an activity required for fertilization (pages 160–166).

One in 50 African-Americans have nonsense mutations in a gene that regulates cholesterol levels, PCSK9, accounting for a substantial lowering of blood LDL-cholesterol.

Viagra operates by increasing the levels of cGMP in target cells. This same mechanism underlies a newly discovered action of the drug in mouse hearts: counteracting hypertrophy (pages 214–222).

The phosphatase SHIP2 has been the focus of drug development efforts for diabetes. This distinction is based in part on work suggesting that the molecule is central to the regulation of glucose levels in tissues and blood. An analysis of a SHIP2 knockout mouse changes this viewpoint and provides new directions for therapeutic intervention (pages 199–205).

For decades cancer biologists have thought of oncogenes in terms of their ability to prompt tumor growth and survival, acting within the cancer cell. That viewpoint is now changing to take into account data showing that oncogenes influence inflammation. Insights now emerge from work on Ras and the proinflammatory mediator interleukin-8, produced by tumor-infiltrating immune cells.

Three studies show that cells are protected against intracellular pathogens by autophagy, a process that degrades cytoplasmic components in bulk. The work may have implications for the development of vaccines against pathogens such as Mycobacterium tuberculosis, Streptococcus pyogenes and Shigella flexneri.

The BCL-6 oncogene can downregulate expression of the p53 tumor suppressor gene in B cell lymphoma. This pathway probably exists to protect normal germinal-center B cells from apoptosis induced by DNA mutations.

New mouse models of ovarian cancer and endometriosis have been created, defining the genetic relationship between these two gynecologic diseases (pages 63–70).

Apoptosis results in the oxidation of membrane lipids on the dying cell. Newly identified oxidized lipids play a dual role: they contribute to the recognition and phagocytosis of dying cells, but may also spur antibody production and inflammation.

Psoriasis develops through interactions between the skin and immune system. The cell-signaling molecule Stat3 now emerges as a bridge between the two, initiating perturbations in the epidermis and generating misguided T-cell responses (pages 43–49).

Mutations in the clock gene Per2 influence alcohol consumption, as revealed by studies in mice and humans. In mice, this effect seems to be mediated by an excess of glutamate in the brain (pages 35–42).