Transcriptional activities of mutant p53: When mutations are more than a loss

Abstract

The dominant oncogenic properties of mutant p53 have been recognized as a phenomenon associated with tumor progression a long time ago, even before it was realized that the major function of wild type p53 is that of a tumor suppressor. Recent advances in this fascinating area in tumor cell biology reveal that the community of mutant p53 proteins is comprised of proteins that are extremely diverse both structurally and functionally, and elicit a multitude of cellular responses that not only are entirely distinct from those mediated by wild type p53, but also vary among different mutant p53 proteins. Aberrant regulation of transcription is one of the mechanisms underlying the ability of some mutant p53 proteins to act as oncogenic factors. Systematic analyses of the transcriptional activities of mutant p53 suggest that not the loss of transcriptional activity as such, but alterations of target DNA selectivity may be the driving force of mutant p53 specific transcription underlying the growth-promoting effects of mutant p53. This article focuses on mechanistic aspects of mutp53 "gain-of-function" with the emphasis on possible mechanisms underlying transcriptional activation by mutp53.

Hsp90 inhibition has opposing effects on wild-type and mutant p53 and induces p21 expression and cytotoxicity irrespective of p53/ATM status in chronic lymphocytic leukaemia cells

“…Thus, mutant p53 can regulate gene expression independently of wt p53 (Kim and Deppert 2004), and transfection of mutant p53 into p53-null cell lines enhances their tumorigenic potential (Dittmer et al, 1993) and renders them resistant to apoptosis (Li et al, 1998;Blandino et al, 1999;Matas et al, 2001). In keeping with these observations, p53-mutant transgenic mice are more prone to cancer than p53 knockout mice (Harvey et al, 1995;Liu et al, 2000).…”

Interactions of mutant p53 with DNA: guilt by association

“…One mode derives from the p53-SSDB activity of wt p53 that is affected unequally by different mutations and underlies the residual wtp53-like transcriptional activity preserved in some p53 mutants (see Menendez et al, 2007, this issue). A distinctly different mode of mutp53:DNA interaction relies on the ability of mutp53 proteins to bind directly and preferentially DNA in a non-linear conformation (reviewed by Kim and Deppert, 2004). This mode, termed DNA structure-selective binding (p53-DSSB) (reviewed by Kim and Deppert, 2004), is persistently exhibited by mutp53 proteins in vitro with artificially constructed DNA structures (Go¨hler et al, 2005;Walter et al, 2005) and is operative in vivo as demonstrated with structurally flexible genomic sequences (Koga and Deppert, 2000;Walter et al, 2005).…”

“…However, except for the residual SSDB activity retained by the core domain of some mutp53 proteins, the principles of DNA recognition by mutp53 proteins and the role of mutp53 DNA binding for the oncogenic activities associated with some mutp53 proteins remains far from being clear. In contrast to the firmly established framework of sequence-specific interactions of wtp53 that rely on the co-coordinated activities of the p53-DBD and the p53-CTD, the relative impact of these two domains on the interaction of mutp53 proteins with non-canonical DNA is still ill defined (reviewed by Sigal and Rotter, 2000;Kim and Deppert, 2004). The major uncertainty concerns the question of whether mutp53 proteins are able to bind DNA specifically despite the SSDB activity of the core domain being lost or impaired.…”

Mutant p53: from guardian to fallen angel?

“…Several different mechanisms, possibly all used by mutant p53 proteins, are discussed in the following chapters. Central to the transcriptional activities of mutant p53 are its interactions with chromatin and DNA, as introduced and discussed in the review by Kim and Deppert (2004). The implication is that interactions of mutant p53 proteins with DNA are complex and may result in different mechanisms of transcriptional modulation.…”

“…Although so far no linear DNA sequence motif has been defined as a mutant p53-specific response element, there is ample evidence that mutant p53 proteins bind to DNA both in vitro and in vivo, with the binding being determined by the structure of the DNA presented in a non-B conformation (reviewed in Kim and Deppert, 2004). Such binding can lead to the transcriptional activation or repression of genes playing important roles in establishing the malignant phenotype of tumour cells.…”