Abstract
Backgroundp53 is a tumor suppressor and potent inhibitor of cell growth. P73 is highly similar to p53 at both the amino acid sequence and structural levels. Given their similarities, it is important to determine whether p53 and p73 function in similar or distinct pathways. There is abundant evidence for negative cross-talk between glucocorticoid receptor (GR) and p53. Neither physical nor functional interactions between GR and p73 have been reported. In this study, we examined the ability of p53 and p73 to interact with and inhibit GR transcriptional activity.ResultsWe show that both p53 and p73 can bind GR, and that p53 and p73-mediated transcriptional activity is inhibited by GR co-expression. Wild-type p53 efficiently inhibited GR transcriptional activity in cells expressing both proteins. Surprisingly, however, p73 was either unable to efficiently inhibit GR, or increased GR activity slightly. To examine the basis for this difference, a series of p53:p73 chimeric proteins were generated in which corresponding regions of either protein have been swapped. Replacing N- and C-terminal sequences in p53 with the corresponding sequences from p73 prevented it from inhibiting GR. In contrast, replacing p73 N- and C-terminal sequences with the corresponding sequences from p53 allowed it to efficiently inhibit GR. Differences in GR inhibition were not related to differences in transcriptional activity of the p53:p73 chimeras or their ability to bind GR.ConclusionOur results indicate that both N- and C-terminal regions of p53 and p73 contribute to their regulation of GR. The differential ability of p53 and p73 to inhibit GR is due, in part, to differences in their N-terminal and C-terminal sequences.
Highlights
The p53 tumor suppressor pathway is inactivated in a majority of human cancers, either through mutation of the p53 gene or alterations of p53 regulators or p53-pathway proteins [1,2]
To examine the basis for this difference, we generated a series of p53:p73 chimeric proteins in which corresponding regions of either protein have been swapped. These studies revealed that N- and C-terminal regions of p53 and p73 contribute to their regulation of glucocorticoid receptor (GR)
GR levels decreased with Dex treatment when expressed alone or with p53 or p73β, and this decrease was partially blocked by MG132
Summary
The p53 tumor suppressor pathway is inactivated in a majority of human cancers, either through mutation of the p53 gene or alterations of p53 regulators or p53-pathway proteins [1,2]. Wild-type p53 is a transcription factor that binds the promoter regions of various target genes in a sequence-specific manner and activates their transcription. Some of these target genes are necessary for p53 to induce cell cycle arrest following stress, such as Waf, which encodes the cyclin-dependent kinase inhibitor protein p21 [3]. Cancer-derived mutations in p53 block its sequence-specific DNA-binding capability, resulting in decreased expression of these growthinhibitory target genes. This can lead to uncontrolled cell growth and eventual carcinogenesis
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