Regulation of the specific DNA binding function of p53

Hupp, Ted R.; Meek, David W.; Midgley, Carol A.; Lane, David P.

doi:10.1016/0092-8674(92)90562-q

Cited by 901 publications

(895 citation statements)

References 73 publications

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“…The positions of complexes consisting of p53 and DNA, or p53 and DNA and antibody, are indicated on the left. An additional band that was consistently observed on longer exposures is marked by an asterisk on the right p53 mutants resembling p53D62-91 J Roth et al antibody 421 to the reaction mix, the bands were supershifted and the binding e ciency was enhanced, as reported previously (Hupp et al, 1992). The relative binding e ciencies among p53, p53D62-91 and p53 M246I were roughly 5 : 1 : 1 in this case (Figure 8b and data not shown).…”

Section: P53d62-91 Inhibits Pig3 Activation In a Dominant Mannersupporting

confidence: 83%

“…On the other hand, these point mutations, when introduced into p53D62-91, did not alter the selective defect of p53D62-91 to activate the PIG3 promoter. Finally, deleting the last 30 amino acids of p53 (resulting in a mutant termed p53D30 (Hupp et al, 1992;Jayaraman et al, 1997)), a region known to be subject to phosphorylation (Meek, 1998) and acetylation (Gu and Roeder, 1997), enhanced the transcriptional activation of both promoters, but the proline-rich region was still required to activate the PIG3 promoter in this background. Thus, modi®cations of the carboxyterminal domain of p53 do not seem to a ect the ability of p53 to activate the PIG3 promoter, nor do they eliminate the need for the proline-rich region of p53 to induce PIG3 transcription.…”

Section: Phosphorylation At Carboxyterminal Residues Does Not Affect mentioning

confidence: 99%

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Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

et al. 2000

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The p53 tumor suppressor protein induces apoptosis through a mechanism that may involve the transcriptional activation of cellular genes, including the PIG3 gene. A p53 protein lacking the proline-rich region (p53D62-91) induces many p53-responsive genes but not PIG3. In parallel, this mutant induces growth arrest but not apoptosis. We show here that the replacement of the N-terminal (amino acids 1 ± 80) or C-terminal (amino acids 344 ± 393) domains of p53 with heterologous domains does not interfere with transcription from the PIG3 promoter, but these chimeras still require the proline-rich region for PIG3 activation. The p53-homolog p73b also activated the PIG3 promoter, but in contrast to p53, the proline-rich domain of p73b (residues 81 ± 113) was dispensable to induce the PIG3 promoter. Some tumor-derived p53-mutants, especially M246I, retained the ability to activate transcription of mdm2 but speci®cally failed to induce the PIG3 promoter, thus resembling p53D62-91. Further, p53D62-91 and p53M246I were defective for induction of apoptosis. Finally, p53D62-91 and p53M246I both showed reduced binding to the DNA of the PIG3 promoter and also to the DNA of the mdm2 and p21 promoters in vitro. Correspondingly, at low expression levels, p53D62-91 and p53M246I poorly activated the mdm2 promoter when compared to wild type p53. Our results suggest that the proline-rich domain of p53 a ects the ability of the central domain to bind DNA. Moreover, some tumor-derived mutations within the central DNA binding domain of p53 mimic the loss of the proline-rich domain.

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Section: P53d62-91 Inhibits Pig3 Activation In a Dominant Mannersupporting

confidence: 83%

Section: Phosphorylation At Carboxyterminal Residues Does Not Affect mentioning

confidence: 99%

Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

et al. 2000

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“…(**) **p19 ARF is from mouse origin. The human homolog is p14 ARF Regulation of p53 exerted by the C-terminal tail of p53 Modi®cations to the carboxy-terminal, including deletion of the last 30 amino-acids (Hupp et al, 1992), protein-binding (Hupp et al, 1992), phosphorylation of Ser 315 , Ser 318 and Ser 393 Wang and Prives, 1995) and recently acetylation by CREB-binding protein (CBP)/p300 (Gu and Roeder, 1997) were shown to enhance sequencespeci®c DNA-binding of wild-type p53, possibly by inhibition of p53's non-sequence-speci®c DNA-binding activity (Anderson et al, 1997). CBP and p300 are closely related histone acetyl-transferases (HATs) that interact with p53 through its amino terminus and function as coactivators for p53-mediated transcription (Avantaggiati et al, 1997;Lill et al, 1997).…”

Section: Regulation Of P53 Functionmentioning

confidence: 99%

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

1999

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“…Full length proteins were expressed and puri®ed as described by Vaziri et al (1997). In each case the indicated amount of protein was incubated with and without monoclonal antibody PAb421 which binds to the C-terminus of p53 and increases the a nity of latent recombinant p53 for its consensus sequence (Hupp et al, 1992). The palindromic p53 recognition sequence, 5'-GGACATGCCCGGGCATGTCC-3', was labelled with g-32 P-ATP with T4 DNA kinase, annealed and puri®ed according to Sambrook et al (1989).…”

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confidence: 99%

Characterization of the oligomerization defects of two p53 mutants found in families with Li–Fraumeni and Li–Fraumeni-like syndrome

et al. 1998

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Recently two germline mutations in the oligomerization domain of p53 have been identi®ed in patients with Li ± Fraumeni and Li ± Fraumeni-like Syndromes. We have used biophysical and biochemical methods to characterize these two mutants in order to better understand their functional defects and the role of the p53 oligomerization domain (residues 325 ± 355) in oncogenesis. We ®nd that residues 310 ± 360 of the L344P mutant are monomeric, apparently unfolded and cannot interact with wild-type (WT) p53. The full length L344P protein is unable to bind sequence speci®cally to DNA and is therefore an inactive, but not a dominant negative mutant. R337C, on the other hand, can form dimers and tetramers, can hetero-oligomerize with WTp53 and can bind to a p53 consensus element. However, the thermal stability of R337C is much lower than that of WTp53 and at physiological temperatures more than half of this mutant is less than tetrameric. Thus, the R337C mutant retains some functional activity yet leads to a predisposition to cancer, suggesting that even partial inactivation of p53 oligomerization is su cient for accelerated tumour progression.

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Regulation of the specific DNA binding function of p53

Cited by 901 publications

References 73 publications

Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

Tumor-derived mutations within the DNA-binding domain of p53 that phenotypically resemble the deletion of the proline-rich domain

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

Characterization of the oligomerization defects of two p53 mutants found in families with Li–Fraumeni and Li–Fraumeni-like syndrome

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