23 October 2005

Nature Cell Biology doi:10.1038/ncb1314

The paradoxical behaviour of Krüppel-like Factor 4 (KLF4) - both a tumour-supressor or oncogenic, depending on the context - is given an explanation in the November issue of Nature Cell Biology. KLF4 regulates genes involved in cell division and embryonic development, and has been implicated in gastro-intestinal cancer as a tumour suppressor. In other settings, such as breast cancer, KLF4 is overexpressed and positively contributes to tumorigenesis.

The team found that KLF4 allows cells to avoid senescence - a process of cellular ageing resulting in loss of cell division. However, KLF4 was also found to be a potent inhibitor of proliferation in normal non-senescing cells. This switch in behaviour is linked to several genes known to have key roles in cell growth and cancer. KLF4 represses the tumour suppressor p53, while at the same time activating the p21CIP1 cell-cycle inhibitor. p21CIP1 function is lost in most cancers. In this context the repression of p53 frees cells from the shackles of this important growth regulator to expose KLF4's hidden growth-promoting potential. This allows for cell transformation, as well as suppression of cell suicide, or apoptosis.

Depletion of KLF4 from breast cancer cells restored expression of the cancer surveillance gene p53 and allowed apoptosis to occur. These data show that overexpression of KLF4 and loss of p21CIP1 co-operate in cancer formation. The study suggests that, depending on the setting, KLF4 is an enticing target for cancer therapy. However, in cases where p21CIP1 is active, inhibition of KLF4 may actually promote cancer formation. This study is a striking example of the importance of thoroughly understanding the molecular role of cancer genes before designing therapeutic approaches.

9 October 2005

Nature Cell Biology doi:10.1038/ncb1313

Keeping an eye on cholesterol can reduce the risk of heart disease and stroke but new research shows how it may also have benefits for warding off Alzheimer's disease. The function of a mysterious protein, how it affects Alzheimer's and its link to cholesterol is reported in the November issue of Nature Cell Biology.

Studies suggest that high cholesterol levels can be linked with increasing levels of a protein called amyloid-beta (AΒ). Accumulation of this protein is a central feature of Alzheimer's and thought to lead to the neuronal dysfunction and death associated with Alzheimer's. Produced in normal cells, AB comes from a larger protein called amyloid precursor protein (APP). The normal function of both remains a mystery but AB's levels increase sharply in Alzheimer's.

Tobias Hartmann and colleagues examined whether APP and AB could affect lipid metabolism. Cells derived from mice, engineered to remove expression of the enzymes that generate AB had higher levels of cholesterol and of another lipid called sphingomyelin. The team pinpointed these effects to altered activities of two key enzymes in the metabolic pathways of these lipids. They also restored normal levels of these lipids and the enzyme activities by treating these cells with AB. The authors concluded that one function of normal APP is in lipid metabolism - a surprising finding. This study also suggest the existence of a loop - AB levels are controlled by lipids and lipids, in turn, control AB levels - so, such a spiralling mechanism could result in the abnormally high AB levels seen in Alzheimer's, having clear consequences for designing therapeutic interventions.