Regulation of p53 stability and activity in response to genotoxic stress

Colman, Michael S.; Afshari, Cynthia A.; Barrett, J. Carl

doi:10.1016/s1383-5742(00)00035-1

Cited by 159 publications

(112 citation statements)

References 72 publications

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“…This is a complex process involving multiple phosphorylation and acetylation events (Sionov and Haupt, 1999;Colman et al, 2000). ROS contribute to p53 activation in many ways.…”

Section: P53 Signalingmentioning

confidence: 99%

“…Normally, the p85 subunit links the signals from activated insulin-like growth factor-1 (IGF1) receptors to Akt through PI3K, an effect usually associated with cell survival (see above). However, increased p85 expression in the absence of receptor coupling may have a dominant negative effect on the signaling cascade from the IGF1 receptor and thus attenuate its survival influence (reviewed in Colman et al, 2000). Furthermore, p53 can downregulate expression of the survival signal IGF-II, while increasing IGF-binding protein 3 (IGFBP3) levels (reviewed in Grimberg, 2000).…”

Section: P53 Signalingmentioning

confidence: 99%

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Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,100

1,596

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Reactive oxygen species (ROS), whether produced endogenously as a consequence of normal cell functions or derived from external sources, pose a constant threat to cells living in an aerobic environment as they can result in severe damage to DNA, protein, and lipids. The importance of oxidative damage to the pathogenesis of many diseases as well as to degenerative processes of aging has becoming increasingly apparent over the past few years. Cells contain a number of antioxidant defenses to minimize fluctuations in ROS, but ROS generation often exceeds the cell's antioxidant capacity, resulting in a condition termed oxidative stress. Host survival depends upon the ability of cells and tissues to adapt to or resist the stress, and repair or remove damaged molecules or cells. Numerous stress response mechanisms have evolved for these purposes, and they are rapidly activated in response to oxidative insults. Some of the pathways are preferentially linked to enhanced survival, while others are more frequently associated with cell death. Still others have been implicated in both extremes depending on the particular circumstances. In this review, we discuss the various signaling pathways known to be activated in response to oxidative stress in mammalian cells, the mechanisms leading to their activation, and their roles in influencing cell survival. These pathways constitute important avenues for therapeutic interventions aimed at limiting oxidative damage or attenuating its sequelae. Published 2002 Wiley‐Liss, Inc.

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“…This is a complex process involving multiple phosphorylation and acetylation events (Sionov and Haupt, 1999;Colman et al, 2000). ROS contribute to p53 activation in many ways.…”

Section: P53 Signalingmentioning

confidence: 99%

Section: P53 Signalingmentioning

confidence: 99%

Cellular response to oxidative stress: Signaling for suicide and survival*

Martindale

Holbrook

2002

Journal Cellular Physiology

2,100

1,596

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“…This RING finger E3 ubiquitin ligase suppresses the transcriptional activation of p53, enhances its nuclear-to-cytoplasmic shuttling, and promotes its ubiquitin-mediated degradation (Haupt et al, 1997;Ashcroft and Vousden, 1999;Freedman et al, 1999;Colman et al, 2000;Momand et al, 2000;Blattner et al, 2002;Li et al, 2003;O'Keefe et al, 2003, and references therein). All of these activities are increased by Mdm2's phosphorylation on Ser 166 and are decreased by mutation of this residue (Mayo and Donner, 2001;Ashcroft et al, 2002).…”

Section: Onzin Overexpression Promotes Growth Survival and Transformentioning

confidence: 99%

Onzin, a c-Myc-repressed target, promotes survival and transformation by modulating the Akt–Mdm2–p53 pathway

et al. 2005

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The c-Myc oncoprotein is a general transcription factor whose target genes dictate the c-Myc phenotype. One such target of c-Myc, 'onzin', is normally expressed at high levels in myeloid cells and is dramatically downregulated in response to c-Myc overexpression. We show here that short hairpin interfering RNA-mediated knockdown of endogenous onzin results in a reduced growth rate and a proapoptotic phenotype. In contrast, onzin overexpression in fibroblasts is associated with an increased growth rate, resistance to apoptotic stimuli, loss of the G2/M checkpoint, and tumorigenic conversion. Onzin-overexpressing cells fail to induce p53 in response to apoptotic stimuli and contain higher levels of the active, phosphorylated forms of Akt1 and, more strikingly, of Mdm2. Using yeast two-hybrid and coimmunoprecipitation assays, we show that onzin directly interacts with both proteins. Green fluorescent protein tagging also confirms directly that Akt1 and Mdm2 colocalize with onzin, although the precise subcellular distribution of each protein is dependent on its relative abundance. Collectively, our results identify onzin as a novel regulator of several p53-dependent aspects of the c-Myc phenotype via its dramatic effect on Mdm2. This is reminiscent of the c-Mycp19 ARF -| Mdm2 pathway and might function as a complementary arm to ensure the proper cellular response to oncogenic and/or apoptotic stimuli.

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“…For example, induction of cyclin-dependent kinase (Cdk) inhibitor p21 WAF1/CIP1 leads to G1 cell cycle arrest. The increased expression of GADD45 and 14-3-3s participate in p53-driven G2 arrest (Colman et al, 2000). A number of p53-induced genes, such as Apaf1, p53AIP1, and proapoptotic members of the Bcl-2 family (Bax, Bid, Noxa, and PUMA), are directly involved in the mitochondria-dependent cell death pathway (Vousden and Lu, 2002).…”

Section: P53-regulated Genes and Cellular Responsesmentioning

confidence: 99%