Measuring a cell's response to stress:the p53 pathway.

<p class="Para" style="box-sizing: border-box; margin: 0px 0px 24px; padding: 0px; word-break: break-word;">The characterization of complex cellular responses to diverse stimuli can be studied by the use of emerging chip-based technologies.</p><p class="Para" style="box-sizing: border-box; margin: 0px 0px 24px; padding: 0px; word-break: break-word; color: rgb(51, 51, 51); font-family: "Open Sans"; font-size: medium; line-height: 25px;">The p53 pathway is critical to maintaining the integrity of the genome in multicellular organisms. The <em class="EmphasisTypeItalic" style="box-sizing: border-box;">p53</em>gene is activated in response to DNA damage and encodes a transcription factor [1], which in turn activates genes that arrest cell growth and induce apoptosis, thereby preventing the propagation of genetically damaged cells. It is the most important known tumor suppressor gene: perhaps half of all human neoplasms have mutations in <em class="EmphasisTypeItalic" style="box-sizing: border-box;">p53</em>, and there is a remarkable concordance between oncogenic mutation and the loss of p53 transcriptional activity [2]. There is also compelling experimental evidence that loss of p53 function (by whatever means) is one of the key oncogenic steps in human cells, along with altered telomerase activity and expression of mutant <em class="EmphasisTypeItalic" style="box-sizing: border-box;">ras</em> [3]. So far, however, relatively few of the genes regulated by p53 have been identified and it is not even known how many binding sites there are for p53 in the genome, although an estimate based on the incidence of the canonical p53 consensus binding site (four palindromic copies of the sequence 5'-PuPuPuGA/T-3', where Pu is either purine) in a limited region suggests there may be as many as 200 to 300, possibly representing the same number of p53-responsive genes [4]. This makes the p53 response an attractive target for the emerging techniques for global analysis of gene expression, and two recent reports [5,6] illustrate the ways in which these techniques can be used to elucidate the spectrum of genes regulated by this key transcription factor. Vogelstein and colleagues [5] have used serial analysis of gene expression (SAGE) to identify 34 genes that exhibit at least a 10-fold upregulation in response to inducible expression of p53; Tanaka <em class="EmphasisTypeItalic" style="box-sizing: border-box;">et al</em>. [6] have used differential display to identify p53R2, a homolog of ribonuclease reductase small subunit (R2) as a target gene, thereby for the first time implicating p53 directly in the repair of DNA damage.</p>