Biological significance of a small highly conserved region in the N terminus of the p53 tumour suppressor protein

Wei Li Liu, Carol Midgley, Charles Stephen, Mark Saville, David P. Lane

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The p53 tumour suppressor protein plays a central role in maintaining genomic integrity in eukaryotic cells. The most significant biological function of p53 is to act as a sequence-specific DNA-binding transcription factor, which can induce the expression of a variety of target genes in response to diverse stress stimuli. The p53 protein contains six highly conserved regions, one of which, termed Box I, is located in the N-terminal transactivation domain (amino acid residues 13 and 26). The second half of the Box I region is crucial for the interaction with the basal transcription machinery and is thus required for p53's activity as a transcription factor. The same region also binds to Mdm2. Since p53 is targeted by Mdm2 for ubiquitin-mediated proteasome-dependent degradation, this region is also essential for the regulation of p53's stability in response to stress signals. Although the first half of Box I is highly conserved, its biological function is not clearly defined. The aim of this study was to characterise this conserved region and investigate its role in the biological functions of p53. We have generated short deletions and point mutations within this region and analysed their effect on p53 function and regulation. Biochemical analyses demonstrate that deletion of residues 13 to 16 significantly increases both the transcriptional transactivation and G2 arrest-inducing activities of murine p53. Residues 13 to 16 appear to function as a regulatory element in p53, modulating p53-dependent transcriptional transactivation and cell-cycle arrest, possibly by affecting the structural stability of the core domain of the protein. In support of this, the deletion was found to induce second-site reversion of the Val135 temperature-sensitive mutant of murine p53.

Original languageEnglish (US)
Pages (from-to)711-731
Number of pages21
JournalJournal of Molecular Biology
Volume313
Issue number4
DOIs
StatePublished - Nov 2 2001
Externally publishedYes

Fingerprint

Tumor Suppressor Protein p53
Transcriptional Activation
Transcription Factors
Sequence Deletion
Eukaryotic Cells
Proteasome Endopeptidase Complex
Ubiquitin
Cell Cycle Checkpoints
Point Mutation
Amino Acids
Temperature
Genes
Proteins

Keywords

  • Box I
  • Growth arrest
  • Mdm2
  • p53
  • Transcriptional transactivation

ASJC Scopus subject areas

  • Virology

Cite this

Biological significance of a small highly conserved region in the N terminus of the p53 tumour suppressor protein. / Liu, Wei Li; Midgley, Carol; Stephen, Charles; Saville, Mark; Lane, David P.

In: Journal of Molecular Biology, Vol. 313, No. 4, 02.11.2001, p. 711-731.

Research output: Contribution to journalArticle

Liu, Wei Li ; Midgley, Carol ; Stephen, Charles ; Saville, Mark ; Lane, David P. / Biological significance of a small highly conserved region in the N terminus of the p53 tumour suppressor protein. In: Journal of Molecular Biology. 2001 ; Vol. 313, No. 4. pp. 711-731.
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