ΔN-p53, a natural isoform of p53 lacking the first transactivation domain, counteracts growth suppression by wild-type p53

Abstract

The tumor suppressor protein p53 is ubiquitously expressed as a major isoform of 53 kD, but several forms of lower molecular weight have been observed. Here, we describe a new isoform, DN-p53, produced by internal initiation of translation at codon 40 and lacking the N-terminal first transactivation domain. This isoform has impaired transcriptional activation capacity, and does not complex with the p53 regulatory protein Mdm2. Furthermore, DN-p53 oligomerizes with full-length p53 (FL-p53) and negatively regulates its transcriptional and growth-suppressive activities. Consistent with the lack of Mdm2 binding, DN-p53 does not accumulate in response to DNA-damage, suggesting that this isoform is not involved in the response to genotoxic stress. However, in serum-starved cells expressing wild-type p53, DN-p53 becomes the predominant p53 form during the synchronous progression into S phase after serum stimulation. These results suggest that DN-p53 may play a role as a transient, negative regulator of p53 during cell cycle progression.

Expression of p53 and p53/47 are controlled by alternative mechanisms of messenger RNA translation initiation

“…These findings are similar to what has previously been reported and indicate that p53EII is only present in a fraction of all cells (Ghosh et al, 2004) and is unlikely to have much to do with the expression of p53/47. And, most importantly, this study and others find that p53/47 is well expressed from the wtp53 mRNA (Hansen et al, 1998;Courtois et al, 2002;Yin et al, 2002).…”

“…In contrast, the translational regulation of the p53 mRNA has with some exceptions remained relatively unexplored. We recently described that the translation of p53 mRNA can be initiated from an alternate AUG codon at position þ 40 giving rise to a 40 amino acid (aa) N-terminally truncated isoform termed p53/47 (Yin et al, 2002), also described as DNp53 (Courtois et al, 2002;Ghosh et al, 2004). The p53/47 does not harbour the most N-terminal p53 transactivating domain (aa 1-40) nor the Mdm2-binding site (aa 17-23) (Kussie et al, 1996), but retains the second transactivation domain (aa 43-63) (Zhu et al, 1998;Venot et al, 1999), the complete central DNA-binding domain and the C-terminal oligomerization domain.…”

“…Additionally, expression of p53/47 in p53-null cells can induce apoptosis, indicating that p53/47 may function autonomously and/or in conjunction with FLp53 to promote p53-directed cellular responses. It has, however, also been suggested that p53/47 behaves solely as an antagonist of p53-mediated growth suppression (Courtois et al, 2002). Although this appears contradictory and the underlying reasons are unclear, it reinforces the idea that the proportion of p53/47 to FLp53 has implications for the cell biological response to p53 activation, a view that is substantiated by a recent transgenic mouse model demonstrating that overexpression of p53/47 leads to p53-dependent cellular senescence and premature ageing (Maier et al, 2004).…”

p53 isoforms gain functions

“…p53/47 and G2 cell cycle arrest p53/47, or NDp53 as it also been named, was the first reported human isoform and it is derived through alternative translation initiation of the p53 mRNA at the second in-frame AUG codon (Courtois et al, 2002;Yin et al, 2002). This renders a p53 product that lacks the first 40 amino acids of the N-terminus, including the binding site for Mdm2, which is within the highly conserved BoxI and the first of the two trans-activation domains.…”

“…However, p53/47 lacks the TA1 domain required to induce p21 CDKN1A/Cip1 and it is, in fact, a potent suppressor of p53-dependent p21 CDKN1A/Cip1 expression. Thus, it has the capacity to prevent a G1/S cell cycle arrest (Courtois et al, 2002). However, p53 activation also leads to a G2/M arrest.…”