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hi all i'm not sure if this relates exclusively to cancer cells but any investigation into the reasons cells die catches my attention janet ------------------------------------------------------------------------ REUTERS: To Induce Apoptosis, p53 Activates Redox Genes ------------------------------------------------------------------------ WESTPORT, Sep 18 (Reuters) - A team of scientists led by Dr. Bert Vogelstein at Johns Hopkins in Baltimore, Maryland, reports in today's issue of Nature a three-step process by which p53 may induce apoptosis [programmed cell death]. Using a colorectal cancer cell line "...infected with a replication-defective adenovirus encoding p53," Dr. Vogelstein and colleagues "...examined in detail the transcripts induced by p53 expression before the onset of apoptosis." They found that, of more than 7,200 transcripts activated by p53, "...only 14 (0.19%) were expressed at levels more than 10-fold greater in p53-expressing than in control cells." An additional 20 transcripts were expressed at levels 10-fold lower than in control cells. Only 2 of the 14 genes activated by p53 have been previously identified as p-53 induced genes, or PIGs, "...and seven had not previously been described at all." However, many were predicted to encode products that generate reactive oxygen species. This prompted further experiments, which suggested a "...three-step model underlying p53's induction of apoptosis." First, "...p53 transcriptionally activates a specific subset of genes, including oxidoreductases, long before any morphological or biochemical evidence of cell death." The activation of these transcripts then leads to an increase in the cellular content of reactive oxygen species. The third step of the model involves "...the oxidative degradation of mitochondrial components, culminating in cell death." Although the model is consistent with observations made by both the Johns Hopkins investigators and other researchers, Dr. Vogelstein and colleagues point out that it leaves "...several unanswered questions." For instance, "...why some cells enter into apoptosis following p53 expression while others undergo a prolonged growth arrest..." remains unknown. The authors speculate that "...different cells have different capacities to cope with generators of oxidative stress, and that cells with a low capacity succumb to apoptosis." Dr. Andrew Wyllie of the University of Edinburgh, UK, points out in a related article in the September 18 issue of Nature that, although Dr. Vogelstein's model is "seductive," it may still be difficult to identify critical death-determining events. Perhaps the answer is among the 14 p53-induced genes, as Dr. Vogelstein and others suggest, or maybe it will be found "...amongst the 20 new genes still to be worked on that are downregulated by p53." Dr. Wyllie suspects that "...the game of molecular whodunit is not yet played out." Nature 1997;389:237-238,300-305. Copyright 1997 Reuters Limited. <http://www.reutershealth.com/news/docs/199709/19970918sca.html> ------------------------------------------------------------------------ LETTER TO NATURE: A model for p53-induced apoptosis ------------------------------------------------------------------------ The inactivation of the p53 gene in a large proportion of human cancers has inspired an intense search for the encoded proteins physiological and biological properties. Expression of p53 induces either a stable growth arrest or programmed cell death (apoptosis). In human colorectal cancers, the growth arrest is dependent on the transcriptional induction of the protein p21WAF1/CIP1 , but the mechanisms underlying the development of p53-dependent apoptosis are largely unknown. As the most well documented biochemical property of p53 is its ability to activate transcription of genes, they examined in detail the transcripts induced by p53 expression before the onset of apoptosis. Of 7,202 transcripts identified, only 14 (0.19%) were found to be markedly increased in p53-expressing cells compared with control cells. Strikingly, many of these genes were predicted to encode proteins that could generate or respond to oxidative stress, including one that is implicated in apoptosis in plant meristems. These observations stimulated additional biochemical and pharmacological experiments suggesting that p53 results in apoptosis through a three-step process: (1) the transcriptional induction of redox-related genes; (2) the formation of reactive oxygen species; and (3) the oxidative degradation of mitochondrial components, culminating in cell death. K Polyak, Y Xia, J L Zweier, K W Kinzler & B Vogelstein A model for p53-induced apoptosis (Letter to Nature) Nature 389, 300 (1997) ------------------------------------------------------------------------ ARTICLE - APOPTOSIS ------------------------------------------------------------------------ p53 protein is a central player in the process that results in the repair or in the death by apoptosis of potentially cancerous cells. New work unveils several genes that are controlled by p53. It gives a tantalizing view of the way in which cell death may be mediated by p53- induced, death-specifying transcripts, which generate a burst of reactive oxygen species (ROS) on the mitochondrial membrane. In turn, ROS activate the final killing mechanism of apoptosis. Further research will show whether this seductive scheme is a true reflection of what happens in p53-determined cell death. Andrew Wyllie Clues in the p53 murder mystery Nature 389, 237-238 (1997) ------------------------------------------------------------------------ [log in to unmask]