p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest

Flatt, Patricia M.; Polyák, Kornélia; Tang, Luo Jia; Scatena, Caroline D.; Westfall, Matthew D.; Rubinstein, Laura A; Yu, Jian; Kinzler, Kenneth W.; Vogelstein, Bert; Hill, Dave E; Pietenpol, Jennifer A.

doi:10.1016/s0304-3835(00)00441-9

Cited by 74 publications

(45 citation statements)

References 29 publications

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“…One possibility is that the survivor cells may have a reduced capacity to activate or increase levels of p53 in response to genotoxic damage. The p53 protein is important in relaying DNA damage-associated signals into apoptosis or growth-arresting responses, through transactivation of numerous apoptosis-and cell cycle-regulating genes [48], for review see [49]. While Cr(VI)-induced apoptosis in human lung fibroblasts (HLF) is dependent on the presence of p53, which is activated in response to Cr(VI) treatment [4,5], upregulation of p53 protein levels in response to Cr(VI) was not altered in the B-5Cr cells.…”

Section: Discussionmentioning

confidence: 99%

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

et al. 2005

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Certain hexavalent chromium [Cr(VI)] compounds are known genotoxic respiratory carcinogens, which induce apoptosis as a predominant mode of cell death. Selection of cells that are resistant to apoptosis may be a factor in tumour progression. We developed sub-populations of telomerasetransfected human fibroblasts (BJ-hTERT) that survived a 99% clonogenically lethal exposure to Cr (VI) (B-5Cr). B-5Cr cells were markedly resistant to apoptosis induced by several agents and exhibited increased clonogenic survival, especially at apoptogenic doses. B-5Cr cells did not exhibit altered cellular uptake of Cr(VI) and retained a normal p53 response to Cr(VI) exposure. We conducted large-scale gene expression analysis at different time-points after a secondary genotoxic Cr(VI) insult in B-5Cr and BJ-hTERT cells using Affymetrix Genechip® human genome arrays. Cr (VI) exposure led to differential regulation of many genes, which affect a diverse set of cellular activities such as transcription, signal transduction, stress response, cell adhesion, DNA repair, apoptosis and cell cycle modulation. We compared Cr(VI)-induced altered gene expression in the B-5Cr cells to that in the parental cells and identified 223, 147 and 204 genes with at least a two-fold difference in expression at 4, 8 and 18 h after exposure, respectively. Cluster analysis by gene function revealed altered expression of genes involved in apoptosis, cell cycle regulation and DNA repair. Our data suggest an alteration in gene expression that may favor cell survival and/or incomplete DNA repair after genotoxic exposure. Selection of cells with altered expression of these genes may constitute the early stages of tumour progression.

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Section: Discussionmentioning

confidence: 99%

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

et al. 2005

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“…A large number of genes demonstrating altered expression upon p53 expression are related to oxidative stress. One upregulated gene, designated PIG3, is involved with the perpetuation of ROS associated with cell death, although PIG3 overexpression itself is not sufficient to induce apoptosis (Flatt et al, 2000). Manganese superoxide dismutase (MnSOD or SOD2), a critical enzyme involved in radical scavenging, is a target of transcriptional repression by p53 (Drane et al, 2001).…”

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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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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“…At 8 and 12 h after transduction, mRNA was isolated as described previously (Flatt et al, 2000) and analysed as described previously (Barbieri et al, 2005). Data were normalized on a per chip basis to the 50th percentile and then normalized on a per gene basis to the median signal.…”

Section: Microarraysmentioning

confidence: 99%

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

et al. 2007

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p53 and p63 belong to a family of sequence-specific transcription factors regulating key cellular processes. Differential composition of the p53 and p63 DNA-binding sites may contribute to distinct functions of these protein homologues. We used SELEX (systematic evolution of ligands by exponential enrichment) methodology to identify nucleic acid ligands for p63. We found that p63 bound preferentially to DNA fragments conforming to the 20 bp sequence 5 0 -RRRC(A/G)(A/T)GYYYRRRC(A/T) (C/T)GYYY-3 0 . Relative to the p53 consensus, the p63 consensus DNA-binding site (DBS) was more degenerate, particularly at positions 10 and 11, and was enriched for A/G at position 5 and C/T at position 16 of the consensus. The differences in DNA-binding site preferences between p63 and p53 influenced their ability to activate transcription from select response elements (REs) in cells. A computer algorithm, p63MH, was developed to find candidate p63-binding motifs on input sequences. We identified genes responsive to p63 regulation that contain functional p63 REs. Our results suggest that the sequence composition of REs could be one contributing factor to target gene discrimination between p63 and p53.

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p53-dependent expression of PIG3 during proliferation, genotoxic stress, and reversible growth arrest

Cited by 74 publications

References 29 publications

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

Resistance to apoptosis, increased growth potential, and altered gene expression in cells that survived genotoxic hexavalent chromium [Cr(VI)] exposure

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

p63 consensus DNA-binding site: identification, analysis and application into a p63MH algorithm

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