Regulation of p53 protein expression in human cancer

Picksley, Steven M.; Hupp, Ted R.; Lü, Xin; Midgley, Carol A.; Vojtěšek, Bořivoj; Lane, David P.

doi:10.1016/0165-4608(94)90250-x

Cited by 36 publications

(49 citation statements)

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“…Mdm-2 binds to an N terminal region of p53 (Chen et al, 1993;Picksley et al, 1994), inhibiting its transcriptional activation function (Momand et al. 1992) and has thus been proposed to regulate p53 by a negative-feedback-loop mechanism (Wu et al, 1993).…”

Section: Discussionmentioning

confidence: 99%

“…It is unlikely that mdm-2 selectively recognises p53 in an active, DNA binding, conformation as it binds equally well to mutant and wild-type proteins . Oligomerisation of p53 is known to be required for mdm-2 binding (Marston et al, 1995) and there is evidence indicating that phosphorylation of sites in the N terminus of p53 may also regulate the interaction (Picksley et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…As mdm-2 binds amino acids 18 ± 23 at the N terminus of p53 and inhibits its sequence-speci®c DNA binding activity (Chen et al, 1993;Picksley et al, 1994), we next determined whether nuclear extracts of VRn.6 cells contain p53-mdm-2 complexes. Immunoprecipitation ( Figure 5) with antibody SMP14 speci®c to the central region of mdm-2 (a.a. 154 ± 167) co-precipitated p53, but this accounted for only *2.5% of the total p53 that could be precipitated by the p53-speci®c antibody pAb421.…”

Section: P53-dependent Mdm-2 Expression In Vh1 Cellsmentioning

confidence: 99%

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Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2

et al. 1997

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: P53-dependent Mdm-2 Expression In Vh1 Cellsmentioning

confidence: 99%

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Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2

et al. 1997

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“…This was not seen when the blot was incubated with diluent alone, indicating that this represents a direct and speci®c association of PCNA with Fen1. Preincubation of the blot with recombinant Fen1 protein also permitted recognition of the 48 kDa band by antibody 3220, even leading to a slight (Picksley et al, 1994;Warbrick et al, 1995). To map precisely the residues of Fen1 to which PCNA binds, a series of biotinylated 20 amino acids peptides (with 15 amino acid overlaps) were synthesized.…”

Section: Direct Interaction Between Fen1 and Pcna Demonstrated In Farmentioning

confidence: 99%

Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair

et al. 1997

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Following genomic damage, the cessation of DNA replication is co-ordinated with onset of DNA repair; this co-ordination is essential to avoid mutation and genomic instability. To investigate these phenomena, we have analysed proteins that interact with PCNA, which is required for both DNA replication and repair. One such protein is p21 Cip1 , which inhibits DNA replication through its interaction with PCNA, while allowing repair to continue. We have identi®ed an interaction between PCNA and the structure speci®c nuclease, Fen1, which is involved in DNA replication. Deletion analysis suggests that p21 Cip1 and Fen1 bind to the same region of PCNA. Within Fen1 and its homologues a small region (10 amino acids) is su cient for PCNA binding, which contains an 8 amino acid conserved PCNA-binding motif. This motif shares critical residues with the PCNA-binding region of p21 Cip1 . A PCNA binding peptide from p21 Cip1 competes with Fen1 peptides for binding to PCNA, disrupts the Fen1-PCNA complex in replicating cell extracts, and concomitantly inhibits DNA synthesis. Competition between homologous regions of Fen1 and p21 Cip1 for binding to the same site on PCNA may provide a mechanism to co-ordinate the functions of PCNA in DNA replication and repair.

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“…It is argued that mdm2 is also a critical cellular inhibitor of p53 function as mdm2 knock out mice are embryonic lethal but this is rescued in a p53 null background (de Oca Luna et al, 1995;Jones et al, 1995). Once induced by p53, the oncoprotein mdm2 is known to interact with, inhibit p53 as well as target p53 for degradation thereby exhibiting negative feedback with respect to p53 activity (Barak et al, 1993;Bottger et al, 1997;Chen et al, 1996b;Haupt et al, 1996Haupt et al, , 1997Lin et al, 1994;Momand et al, 1992;Oliner et al, 1993;Picksley et al, 1994). p53 has also been shown to repress many cellular and viral promoters which do not contain p53 binding sites (Ko and Prives, 1996).…”

Section: Introductionmentioning

confidence: 99%

mdm2: a bridge over the two tumour suppressors, p53 and Rb

et al. 1999

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The inactivation of the p53 and Rb pathways would account for the majority of human tumours. There are many levels of cross talk between p53 and Rb that have been identi®ed. However, the identi®cation of the mdm2-Rb interaction established a closer link between the two most well studied tumour suppressors, p53 and Rb. Recent studies of the novel trimeric complex Rb-mdm2-p53 provided us with a functional insight of how the two tumour suppressors can act together in regulating p53 induced apoptosis. Beginning with the properties of the Rb-mdm2-p53 trimeric complex, we shall review the propounding evidence suggesting that the apoptotic function of p53 is linked to its transrepression function. The uncoupling of the apoptotic function and transactivation function of p53 will also be discussed.

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Regulation of p53 protein expression in human cancer

Cited by 36 publications

References 0 publications

Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2

Tolerance of high levels of wild-type p53 in transformed epithelial cells dependent on auto-regulation by mdm-2

Homologous regions of Fen1 and p21Cip1 compete for binding to the same site on PCNA: a potential mechanism to co-ordinate DNA replication and repair

mdm2: a bridge over the two tumour suppressors, p53 and Rb

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