The role of the C' terminus of murine p53 in the p53/mdm-2 regulatory loop

Abstract

Mdm-2 plays a central role in the regulation of p53 protein level and activity. Although the interaction of mdm-2 and p53 occurs through the N-terminus of the p53 protein, our present data suggest that the C' terminus plays an important role in the regulation of the p53/mdm-2 loop. Comparative analysis of the murine regularly spliced form of p53 (RSp53) and a physiological C-terminally modified p53 protein, which results from alternative splicing of the p53 mRNA (ASp53), indicated that the two isoforms behave differently in the p53/mdm-2 loop. We found that ASp53 can preferentially induce higher levels of the mdm-2 protein, compared with RSp53. Although the transactivation capacity of both forms is inhibited by mdm-2, only RSp53 is directed to proteolytic degradation by mdm-2, while ASp53 is relatively resistant. We present evidence that suggests that ASp53 protein levels determine the biological activities mediated by RSp53, such as the induction of apoptosis, through the mdm-2/p53 regulatory loop. We suggest, therefore, a new mechanism for the regulation of p53, and show that alteration of the p53 extreme C' terminus can significantly change the transcription activity and the resistance to degradation properties of the p53 protein.

Overexpression of microRNA-125a-3p effectively inhibits the cell growth and invasion of lung cancer cells by regulating the mouse double minute 2 homolog/p53 signaling pathway

“…Mouse double minute 2 homolog (MDM2), also termed E3 ubiquitin-protein ligase (17,18), is an important negative regulator of the p53 tumor suppressor. Mdm2 protein recognizes the N-terminal trans-activation domain of the p53 tumor suppressor and inhibits p53 transcriptional activity (19,20). The p53-MDM2 signaling pathway is known to control cancer invasion and metastasis (21).…”

p53 Isoforms: An Intracellular Microprocessor?

“…53 Indeed, p53AS is a less potent transactivator of Bax and p21 promoters, although p53AS has a stronger affinity to p53REs. , 42 Kulesz-Martin et al, 45 Wu et al, 43 Miner and Kulesz-Martin, 49 Wu et al, 47 Almog et al, 53 Wolkowicz et al, 48 Almog et al, 54 Almog et al, 55 and Huang et al…”

“…54 The p53AS inhibitory effect on p53-mediated apoptosis is MDM2 dependent, as p53AS is able to induce higher levels of the MDM2 protein than p53. 55 Although p53AS was shown to regulate the expression of several genes including p21, Bax, and Bcl-2, Kulesz-Martin and colleagues reported that p53AS is more effective in transcription repression than p53, highlighting a role of p53 C-terminal domain in this effect. 44 Mouse Δ40p53 isoform (also named ΔNp53 or p44) is expressed in normal tissue through alternative initiation of translation at codon 41.…”