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Interfer-ing with Myelin

Inflammatory reactions in the central nervous system play important roles in the pathogenesis of white matter diseases such as multiple sclerosis and periventricular leukomalacia. These reactions result in the exposure of oligodendrocytes to various cytokines that affect oligodendroglial survival, proliferation, and differentiation. One of these cytokines, interferon- (IFNG), has been reported to have both a deleterious and protective role on myelin synthesis. These conflicting observations prompted Makoto Horiuchi and colleagues to investigate the effects of interferon- on rat oligodendroglial cultures at different developmental stages.

IFNG induces cell death in oligodendroglial progenitor cells.

In this Paper of the Week, the researchers show that simultaneous activation of the signal transducers and activator of transcription (STAT) pathway by interferon- and of the extracellular signal-regulated kinase (ERK) pathway by exogenous trophic factors plays a role in interferon-induced cytotoxicity in proliferating oligodendroglial progenitors. The effect is developmental stage-specific in that non-proliferating immature and mature oligodendrocytes are protected from interferon-induced cell death. This comprehensive study is of considerable importance and relevance to inflammation-induced demyelinating disease.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 20095-20106

Trapped p53 Reveals Dimeric Structure

p53 is a transcription factor that regulates the cell cycle and thus functions as a tumor suppressor. It responds to cellular stresses such as DNA damage, in part, by binding to DNA and regulating the transcription of genes involved in cell cycle arrest, apoptosis, or senescence. In its active form, p53 forms a dimer of dimers. However, the only structural information about the mode of DNA recognition by p53 was provided over a decade ago when the structure of the p53 core domain monomer bound to DNA was determined.

Model of a p53DBD tetramer bound to icosamer DNA.

In this Paper of the Week, William C. Ho and colleagues use a cross-linking strategy to trap a p53 core domain dimer bound to DNA for structure determination by x-ray crystallography. Their 2.3 Å structure reveals the molecular details of cooperative dimeric p53 binding to DNA that involves a zinc-binding domain. The researchers also discovered that a hot spot for tumor-derived mutations maps to the dimerization region, reinforcing its functional importance. Interestingly, residues associated with p53 dimer formation on DNA are poorly conserved in the p63 and p73 paralogs, possibly due to their functional differences. Ho et al. also used the dimeric protein-DNA complex to model a dimer of p53 dimers bound to icosamer DNA. Their model suggests that the p53 core domain dimer-dimer contacts are less frequently mutated in human cancer than intra-dimer contacts.

FOOTNOTES

See referenced article, J. Biol. Chem. 2006, 281, 20494-20502

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