Evidence has grown over the last few years for the involvement of the tumor suppressor protein p53 in the neuronal cell death that accompanies a variety of neurodegenerative diseases, including Alzheimer's disease (see de la Monte et al. and related news item). Now, researchers describe in the online Journal of the American Chemical Society the synthesis of a range of inhibitors that may help retard or halt p53-mediated cell death.
Led by Nigel Greig, first author Xiaoxiang Zhu and colleagues at the National Institute on Aging, Baltimore, Maryland, and Indiana University School of Medicine in Indianapolis, used pifithrin-α, a known p53 inhibitor, as a starting point for the development of more potent neuroprotective compounds. Zhu et al. tested 16 derivatives in a cell death assay of PC12 neurons challenged with the DNA-damaging agent camptothecin. IC50s, the concentration required to achieve 50 percent protection, ranged from a high of almost 9 μM to 70 nM for these compounds, none of which appeared to be toxic to the cells.
Zhu et al. found that these derivatives were also effective in protecting primary hippocampal neurons against camptothecin and its analogue etoposide, and that they improved the survival of neurons exposed to glutamate, while pifithrin-α itself protected mice against neuronal loss following experimentally induced stroke.
Meanwhile, results from Kun Ping Lu's lab at Harvard Medical School seem to strengthen the case for p53’s involvement in AD. In the online Journal of Biological Chemistry, first author Gerburg Wulf and coworkers show that the prolyl isomerase Pin1, which has been vaguely implicated in the etiology of the disease (see related news item), mediates DNA damage-induced stabilization of the tumor suppressor.
This stabilization is necessary to keep p53 around long enough to cause cell cycle arrest and thus fulfill its suppressor function. Wulf et al. show that when Pin1 null cells are irradiated to damage their DNA, p53 fails to accumulate, as it normally does in wild-type cells. In addition, these cells fail to stimulate p21, the downstream target of p53, and they continue to cycle.
How Pin1 affects these molecular and cellular changes is unclear. However, given that the interaction between Pin1 and p53 depends on the presence of amino acids serine 33 and serine 46 in p53, the authors propose that following phosphorylation of these residues, Pin1 isomerizes their proximal prolines 35 and 48, resulting in a conformational change that may increase the stability of p53 and its activity on the p21 promoter.—Tom Fagan
- de la Monte SM, Sohn YK, Wands JR. Correlates of p53- and Fas (CD95)-mediated apoptosis in Alzheimer's disease. J Neurol Sci. 1997 Nov 6;152(1):73-83. PubMed.
- Zhu X, Yu QS, Cutler RG, Culmsee CW, Holloway HW, Lahiri DK, Mattson MP, Greig NH. Novel p53 inactivators with neuroprotective action: syntheses and pharmacological evaluation of 2-imino-2,3,4,5,6,7-hexahydrobenzothiazole and 2-imino-2,3,4,5,6,7-hexahydrobenzoxazole derivatives. J Med Chem. 2002 Nov 7;45(23):5090-7. PubMed.
- Wulf GM, Liou YC, Ryo A, Lee SW, Lu KP. Role of Pin1 in the regulation of p53 stability and p21 transactivation, and cell cycle checkpoints in response to DNA damage. J Biol Chem. 2002 Dec 13;277(50):47976-9. PubMed.