p53: a transdominant regulator of transcription whose function is ablated by mutations occurring in human cancer.

Abstract

Gal4‐p53 fusion constructs demonstrate that wild type p53 is a potent transactivator in human lung cancer cells with the transactivation domain for p53 residing in amino acids 1–42. Strikingly, a variety of lung cancer derived p53 mutations occurring outside this domain disrupt this activity. Temperature sensitive conformational shifts of p53 mutant proteins to the wild type form exist and, with a temperature downshift, several mutants become transcriptionally active. Wild type p53 protein is known to form oligomers with mutant p53 and cotransfection of wild type and mutant genes shows that p53 acts in a transdominant manner that is independent of the DNA binding specificity. Transcription is either increased or decreased depending on whether the wild type is more or less abundant than the mutant form. Finally, lung cancers differ in their ability to support the transactivation related functions, providing evidence of other abnormalities of the p53 system in human cancer.

Twenty years of p53 research: structural and functional aspects of the p53 protein

“…The N-terminal region contains the activation domain (amino acid 1 ± 42) (Fields and Jang, 1990;Unger et al, 1992) although neighbouring sequences are probably needed for the activation domain to function optimally. The acidic Nterminal transcriptional domain allows p53 to recruit the basal transcriptional machinery, including the TATA box binding protein (TBP) and TBP-associated factors (TAF) components of TFIID (Lu and Thut et al, 1995).…”

Isolation of canine p53 cDNA and detailed characterization of the full length canine p53 protein

“…Consistent with this role for p53, our results demonstrate that canine p53 protein can function as an e cient transcription activator in p53 null primary murine embryo ®broblast cells (see Figure 7). Similar to human p53 protein (Unger et al, 1992(Unger et al, , 1993, the transactivation activity of canine p53 protein is localized within the N-terminal domain. Conservation of amino acid residues phenylalanine 19, leucine 22, and tryptophan 23 within the N-terminus of the canine p53 protein may contribute to the transactivation potential of canine p53 protein (Lin et al, 1995).…”

“…Transfection of canine or murine p53 cDNA resulted in a similar upregulation of b-galactosidase expression in 18MEF cells when compared with the vector-only control (Figure 7). The transactivation activity of the p53 protein has previously been localized to the ®rst 43 amino acid residues of the Nterminal domain (Unger et al, 1992). To determine if the transactivation activity of canine p53 protein was located within the N-terminal domain, we constructed a canine p53 mutant lacking the ®rst 68 amino acids (cp53DN).…”

Regulation of p53 activity by HIPK2: molecular mechanisms and therapeutical implications in human cancer cells

“…This feedback loop, in which p53 upregulates MDM2 expression, whereas MDM2 downregulates p53 activity, is essential for restraining p53 function in nonstressed cells and probably for eliminating accumulated p53 after successful completion of DNA repair. Several studies have shown that DNA-damage-induced phosphorylation of serine and a threonine residues at the N-terminus contributes to p53 stability by preventing MDM2 from proteasomal degradation (Unger et al, 1992;Shieh et al, 1997). In this regard, HIPK2-induced p53 phosphorylation changes the interaction between MDM2 and p53, prevents the MDM2-mediated cytoplasmic shuttling and ubiquitination of p53 in response to genotoxic agents and recovers the p53 apoptotic function (Di Stefano et al, 2004b).…”