Negative feedback regulation of wild-type p53 biosynthesis.

Abstract

When growth‐arrested mouse fibroblasts re‐entered the cell‐cycle, the rise in tumour suppressor p53 mRNA level markedly preceded the rise in expression of the p53 protein. Furthermore, gamma‐irradiation of such cells led to a rapid increase in p53 protein biosynthesis even in the presence of the transcription inhibitor actinomycin D. Both findings strongly suggest that p53 biosynthesis in these cells is regulated at the translational level. We present evidence for an autoregulatory control of p53 expression by a negative feed‐back loop: p53 mRNA has a predicted tendency to form a stable stem‐loop structure that involves the 5′‐untranslated region (5′‐UTR) plus some 280 nucleotides of the coding sequence. p53 binds tightly to the 5′‐UTR region and inhibits the translation of its own mRNA, most likely mediated by the p53‐intrinsic RNA re‐annealing activity. The inhibition of p53 biosynthesis requires wild‐type p53, as it is not observed with MethA mutant p53, p53‐catalysed translational inhibition is selective; it might be restricted to p53 mRNA and a few other mRNAs that are able to form extensive stem‐loop structures. Release from negative feed‐back regulation of p53 biosynthesis, e.g. after damage‐induced nuclear transport of p53, might provide a means for rapidly increasing p53 protein levels when p53 is required to act as a cell‐cycle checkpoint determinant after DNA damage.

Cytoplasmic retention of mutant tsp53 is dependent on an intermediate filament protein (Vimentin) scaffold

“…Indeed, there is ample evidence for a functiondependent localization of p53 to either cellular compartment. When resting cells resume cycling, wt p53 remains in the cytoplasm during G1 phase, but is translocated into the nucleus at the onset of S-phase (Shaulsky et al, 1990a), in accordance with a role of wt p53 in translational control of its own mRNA in G1 (Mosner et al, 1995). During di erentiation of neurons and oligodendrocytes explanted from embryonic rat brain, wt p53 is translocated into the nucleus and is relocated to the cytoplasm in di erentiated cells (Eizenberg et al, 1996).…”

p53 protein stability in tumour cells is not determined by mutation but is dependent on Mdm2 binding

“…Instability of mouse p53 in MCF7 is not due to inhibition of translation (Mosner et al, 1995) have demonstrated the inhibition of translation of p53 mRNA by wild-type p53 protein.…”

“…This might be the mechanism for selection of mutant p53 cell clones which survive hypoxic stress and eventually colonise the tumour leading to malignancy. A novel mechanism which may relate to p53 induction has been described by Mosner et al (1995). They have demonstrated that wild-type p53 protein can inhibit the translation of its own messenger RNA by binding to a putative stem loop structure in the 5' untranslated region.…”

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

“…Mosner et al (1995) showed a negative feedback regulation of p53 on its own synthesis. The p53 mRNA can form a stable stemloop structure that involves the 5'-untranslated region (5'-UTR) as well as some 280 nucleotides of the coding sequence.…”