Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Upon cellular DNA damage, the p53 tumor suppressor protein transmits a signal to genes that control the cell cycle and apoptosis. One function of p53 that is important for its role in this pathway is its ability to function as a sequence-specific transcriptional activator. We demonstrate here that short single DNA strands can markedly stimulate the ability of human and murine p53 proteins to bind specifically to a p53 response element in supercoiled DNA. We also show that single-stranded DNA does not stimulate binding by a truncated p53 that lacks the C-terminal domain. Finally, we establish that a peptide spanning the p53 C-terminus has the ability in trans to stimulate sequence-specific DNA binding by p53 dramatically. These data taken together suggest a model in which the p53 C-terminus can recognize DNA structures resulting from damage-induced lesions, and this interaction can be propagated to regulate positively p53 sequence-specific DNA binding.
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PMID:Activation of p53 sequence-specific DNA binding by short single strands of DNA requires the p53 C-terminus. 760 May 71

The p53 tumour suppressor protein is a transcriptional activator, which can induce cell cycle arrest and apoptosis. p53 Gene mutations occur in more than 50% of all human tumours. Reintroduction of wild-type p53 but also of oligomerisation-independent p53 variants into tumour cells by gene transfer methods has been considered. We have investigated the biological properties of two carboxy-terminal deletion mutants of p53, p53 delta 300 (comprising amino acids 1-300) and p53 delta 326 (amino acids 1-326), to evaluate their potential deployment in gene therapy. Transactivation was measured in transiently transfected HeLa and SKBR3 cells. Both monomeric variants showed reduced activities compared with wild-type p53. Individual promoters were differently affected. In contrast to wild-type p53, monomeric variants were not able to induce apoptosis. We also provided wild-type p53 and p53 delta 326 with tetracycline-regulated promoters and stably introduced these constructs into Saos2 and SKBR3 cells. Upon induction, wild-type p53 expressing cells, but not p53 delta 326 expressing cells underwent apoptosis. Consistently, only wild-type p53 expressing cells accumulated p21/waf1/cip1 mRNA and protein and showed increased bax, Gadd45 and mdm2 mRNA. Neither wild-type p53 nor p53 delta 326 repressed the transcription of the IGF-1R gene in these cell lines. We conclude that the transactivation potential of monomeric, carboxy-terminally truncated p53 is not sufficient to cause induction of the endogenous target genes which trigger apoptosis.
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PMID:Transcriptional regulation and induction of apoptosis: implications for the use of monomeric p53 variants in gene therapy. 1002 42