Increase in p53 protein half-life in mouse keratinocytes following UV-B irradiation

Liu, Ming; Dhanwada, Kavita R.; Birt, Diane F.; Hecht, Scott; Pelling, Jill C.

doi:10.1093/carcin/15.6.1089

Cited by 76 publications

(57 citation statements)

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“…Moreover this reasoning suggests that the latent p53 with a lifetime of about 20 min and its slow oligomerization kinetics (26,27) is unlikely to yield significant occupancy in tetrameric form at hundreds of target promoters. The search, however, is fast enough to allow a long-lived activated form (lifetime of ∼200 min) (28,29) to bind most of target promoters.…”

Section: Discussionmentioning

confidence: 99%

A single-molecule characterization of p53 search on DNA

Tafvizi

Huang

Fersht

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

226

301

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The tumor suppressor p53 slides along DNA while searching for its cognate site. Central to this process is the basic C-terminal domain, whose regulatory role and its coordination with the core DNAbinding domain is highly debated. Here we use single-molecule techniques to characterize the search process and disentangle the roles played by these two DNA-binding domains in the search process. We demonstrate that the C-terminal domain is capable of rapid translocation, while the core domain is unable to slide and instead hops along DNA. These findings are integrated into a model, in which the C-terminal domain mediates fast sliding of p53, while the core domain samples DNA by frequent dissociation and reassociation, allowing for rapid scanning of long DNA regions. The model further proposes how modifications of the C-terminal domain can activate "latent" p53 and reconciles seemingly contradictory data on the action of different domains and their coordination.recognition | response element | transcription factor

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Section: Discussionmentioning

confidence: 99%

A single-molecule characterization of p53 search on DNA

Tafvizi

Huang

Fersht

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

226

301

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“…The UV-induced phosphorylation of Egr-1 involves both the PKC and tyrosine kinase pathways because the inhibition of these kinase activities significantly reduced Egr-1 phosphorylation ( Figure 7B), transactivating ability (Figures 8 and 9) and cell survival after UV (Figure 10). In mammalian cells, UV exposure turns on the UV response process which is characterized by increased levels of transcription factors including Egr-1 and AP-1 and increased stabilization of p53 (Liu et al, 1994). The biological function of the mammalian UV response is just beginning to be understood.…”

Section: Discussionmentioning

confidence: 99%

Egr-1 inhibits apoptosis during the UV response: correlation of cell survival with Egr-1 phosphorylation

et al. 1998

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UV irradiation of normal or immortalized cells induces a rapid increase in the expression of several transcription factors and is thought to serve a protective function. The human fibrosarcoma cell line, HT1080 clone H4, expresses almost undetectable levels of Egr-1 and does not respond to UV-C irradiation by the induction of Egr-1. The H4 cells are hypersensitive to UV which induces apoptosis and reduces clonogenicity. The introduction of exogenous Egr-1 into H4 (H4E9 and H4E4 cell-lines) confers protection from UV damage as measured by a number of assays. In both NIH3T3 (with inducible Egr-1) and H4E9 (constitutive Egr-1) cells, UV irradiation gave enhanced transactivation of Egr-1 reporters that correlated with phosphorylated Egr-1. Studies using inhibitors indicated that protein kinase-C and tyrosine kinases are involved in the anti-apoptotic effects of Egr-1 after UV damage. This is the first description of a biological effect of phosphorylated Egr-1.

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“…In addition, u.v. stabilized wt p53 in wild-type conformation (Liu et al, 1994). A dominant-negative e ect also does not explain the stabilization of wt p53 that accompanies interaction with viral oncoproteins.…”

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confidence: 83%

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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Increase in p53 protein half-life in mouse keratinocytes following UV-B irradiation

Cited by 76 publications

References 0 publications

A single-molecule characterization of p53 search on DNA

A single-molecule characterization of p53 search on DNA

Egr-1 inhibits apoptosis during the UV response: correlation of cell survival with Egr-1 phosphorylation

Loss of function and p53 protein stabilization

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