Identification and classification of p53-regulated genes

Abstract

Sequence-specific transactivation by p53 is essential to its role as a tumor suppressor. A modified tetracycline-inducible system was established to search for transcripts that were activated soon after p53 induction. Among 9,954 unique transcripts identified by serial analysis of gene expression, 34 were increased more than 10-fold; 31 of these had not previously been known to be regulated by p53. The transcription patterns of these genes, as well as previously described p53-regulated genes, were evaluated and classified in a panel of widely studied colorectal cancer cell lines. ''Class I'' genes were uniformly induced by p53 in all cell lines; ''class II'' genes were induced in a subset of the lines; and ''class III'' genes were not induced in any of the lines. These genes were also distinguished by the timing of their induction, their induction by clinically relevant chemotherapeutic agents, the absolute requirement for p53 in this induction, and their inducibility by p73, a p53 homolog. The results revealed substantial heterogeneity in the transcriptional responses to p53, even in cells derived from a single epithelial cell type, and pave the way to a deeper understanding of p53 tumor suppressor action.

Gene expression of cyclin‐dependent kinase subunit Cks2 is repressed by the tumor suppressor p53 but not by the related proteins p63 or p73

“…Expression of Cks2 mRNA is downregulated after increased p53 expression The human colorectal adenocarcinoma cell line DLD-1 is negative for functional p53 protein. We employed a stably transfected DLD-1 cell line which allows for tet-off-regulated expression of wild-type p53 [8,20]. In control experiments we had confirmed that after tet-off induction for 9 h expression of p53 mRNA and protein increases [8].…”

“…Parental HCT116 cells and HCT116 cells with targeted deletion in both p53 alleles [19] as well as inducible cell line D.P53 A2 (DLD-1-tet-off-p53) was generously provided by Vogelstein [20]. The latter cell line is a derivative of the colorectal carcinoma cell line DLD-1, which has endogenous mutant p53 alleles.…”

p53 promotes cellular survival in a context-dependent manner by directly inducing the expression of haeme-oxygenase-1

“…In this context, HO-1 stands out, with its antioxidant properties (Ferris et al, 1999;Petrache et al, 2000;Fang et al, 2004;Gozzelino et al, 2010). It is noteworthy that HO-1 was noted to be induced by overepxressed p53 a decade ago by Vogelstein and co-workers, although they concluded that upon stress treatment with doxorubicin and 5-fluorouracial, HO-1 was not induced in a p53-dependent manner (Yu et al, 1999). Recently, when our work was underway, a report showed that HO-1 can be induced in a p53-dependent manner in mouse lymphoid tissues (Meiller et al, 2007), although the physiological consequences were not reported.…”

Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

“…In contrast, no such C-terminal proline-rich domain is found in p53, and the reported interactions of p53 with c-abl (Sionov et al, 1999) were thus proposed to be of a more indirect nature (White and Prives, 1999). A recent report (Yu et al, 1999) concluded that p73 was unable to activate the PIG3 promoter. It should be noted, however, that the a form of p73 was used there, whereas the b form was used in our study.…”