Wild-type p53 activates transcription in vitro

Farmer, George; Bargonetti, Jill; Zhu, Hua; Friedman, Paula N.; Prywes, Ron; Prives, Carol

doi:10.1038/358083a0

Cited by 555 publications

(344 citation statements)

References 24 publications

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“…Therefore we in our following experiments used oligonucleotides that contained only one copy of the RGC half-site. Although the RGC-site usually is used in a multimeric form, a half-site alone is su cient for binding and transactivation by p53 in vitro (Farmer et al, 1992;Kern et al, 1992). Due to the lack of a second symmetric half-site, a single RGC binding site does not have the ability to adopt an alternative conformation by itself.…”

Section: Comparative Analysis Of Natural P53 Binding Sitesmentioning

confidence: 99%

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

1997

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Sequence-speci®c transactivation of target genes is one of the most important molecular properties of the tumor suppressor p53. Binding of p53 to its target DNAs is tightly regulated, with modi®cations in the carboxyterminal regulatory domain of the p53 protein playing an important role. In this study we examined the possible in¯uence of DNA structure on sequence-speci®c DNA binding by p53, by analysing its binding to p53 consensus elements adopting di erent conformations. We found that p53 has the ability to bind to consensus elements which are present in a double-helical form, as well as to consensus elements which are located within alternative non-B-DNA structures. The ability of a consensus element to adopt either one of these conformations is dependent on its sequence symmetry, and is strongly in¯uenced by its sequence environment. Our data suggest a model according to which the conformational status of the target DNA is an important determinant for sequence-speci®c DNA binding by p53. Modi®cations in the carboxy-terminal regulatory region of p53 possibly determine the preference of p53 for a given DNA conformation.

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Section: Comparative Analysis Of Natural P53 Binding Sitesmentioning

confidence: 99%

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

1997

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“…Three viral oncoproteins have been reported to inhibit p53 function and increase its levels: (1) Ad E1b, a 55-kD protein, forms a complex with p53, disrupting its trans-activational activity but also leading to its stabilization (Lane and Crawford, 1979; Linzer and Levine, 1979;Oren et al, 1981;Sarnow et al, 1982;Braithwaite and Jenkins, 1989;Yew and Berk, 1992). (2) SV40 large T antigen binds to p53 eliminating wt p53 speci®c functions and stabilizes p53 (Braithwaite and Jenkins, 1989;Farmer et al, 1992). Although large T antigen can form complexes with p53, free p53 is also stable (Deppert and Haug, 1986;Deppert and Steinmayer, 1989).…”

Section: Inactivation By Oncoproteins Stabilizes Wt P53mentioning

confidence: 99%

“…Although these proteins are very di erent, the common outcome is the loss of p53 function, not complex formation (Farmer et al, 1992;Deppert et al, 1987). Complex formation with T antigen (and HSP70) does not directly stabilize p53 (Halevy et al, 1989).…”

Section: Inactivation By Oncoproteins Stabilizes Wt P53mentioning

confidence: 99%

Loss of function and p53 protein stabilization

Blagosklonny

1997

Oncogene

127

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Wild-type (wt) p53 protein is rapidly degraded, has a short half-life and low intracellular levels. Stabilization of wt p53 protein following an appropriate stimulus (for example DNA damage) is a physiological regulation to increase function. In contrast, stabilization of p53 protein in the absence of a stimulus is always a hallmark of loss of function secondary to a mutation, or interaction with viral or cellular oncoproteins. It is generally accepted that stability of p53 protein depends on its intrinsic biochemical properties such as conformation or protein/protein interactions. However, I will discuss evidence that the stability of p53 is not a consequence of its intrinsic properties, but instead is determined by feedback control of its function. In the absence of an appropriate stimulus, a cell needs to keep p53 levels low, since increased levels can lead to apoptosis. To precisely regulate p53 levels, a cell must sense its level; and sensing its transactivating function, is the simplest way to sense p53. Following an appropriate stimulus (for example, DNA damage), the cell senses a state of`relative' p53 de®ciency and adapts by reducing p53 degradation. When the state of p53 de®ciency is a consequence of a mutation or interaction with viral oncoproteins, the cell does not sense p53, and again attempts to adapt by reducing p53 degradation. However, in the latter case, the increase in levels does not restore function, and the adaptation continues until degradation of p53 protein is maximally inhibited. In this case, no further inhibition of degradation is possible after DNA-damage or pharmacological inhibition of proteasomes. Thus lack of wt p53 function always results in increased p53 levels and nonregulation.

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“…Moreover, the level of p53 can also be modulated at the transcriptional level after mitogenic stimulation, di erentiation induction and genotoxic stress (Reich and Levine, 1984;Sun et al, 1995;Balint and Reisman, 1996;Kirch et al, 1999). The WT-activated p53 acts as a transcriptional factor and regulates the expression of target genes including p21(WAF1/CIP1), gadd45, bax or bcl2, which in turn control cell cycle checkpoints, DNA repair and apoptosis (Kern et al, 1991;Farmer et al, 1992;Miyashita et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

et al. 2000

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The tumor suppressor p53 plays a pivotal role in the cellular response to DNA damage as it controls DNA repair, cell cycle arrest and apoptosis. We studied the autoregulation of human p53 gene transcription in colon cancer cell lines. Wild-type p53 has been shown to autoregulate its own transcription either positively or negatively and probably in a cell-type-speci®c manner. Indeed, a p53 binding site has been described in the human and murine p53 promoters, but a direct binding of wild-type p53 protein to this site has never been reported.In this study, we demonstrated a transactivation of human p53 promoter by wild-type p53 in human colon cancer cells. We identi®ed in the human p53 promoter a novel potential p53-responsive element that binds wildtype p53. Moreover, wild-type p53 protein transactivated a reporter plasmid containing a luciferase gene driven by a minimal promoter harboring this p53 binding site. Finally, as the p53 promoter contains an NF-kB binding site, we demonstrated an additive e ect when NF-kB subunits and p53 protein combined to transactivate the human p53 promoter. Oncogene (2000) 19, 4787 ± 4794.

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Wild-type p53 activates transcription in vitro

Cited by 555 publications

References 24 publications

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

DNA-conformation is an important determinant of sequence-specific DNA binding by tumor suppressor p53

Loss of function and p53 protein stabilization

Additive effect between NF-κB subunits and p53 protein for transcriptional activation of human p53 promoter

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