UV Radiation Is a Transcriptional Inducer of p21Cip1/Waf1Cyclin-Kinase Inhibitor in a p53-Independent Manner

Haapajärvi, Tarja; Kivinen, Laura; Heiskanen, Annamari; Bordes, Charles Des; Datto, Michael B.; Wang, Xiao Fan; Laiho, Marikki

doi:10.1006/excr.1999.4403

Cited by 52 publications

(39 citation statements)

References 39 publications

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“…These results suggest that p53 transactivates its target genes di erentially in a DNA damage-dependent manner. However, though these are known p53 target genes, we cannot exclude that some of the regulation also takes place independently of p53 (Loignon et al, 1997;HaapajaÈ rvi et al, 1999).…”

Section: Discussionmentioning

confidence: 97%

“…Doses of UVC were chosen on the basis of previous reports (Perry et al, 1993;Wu and Levine, 1997;Reinke and Lozano, 1997;McKay et al, 1998;HaapajaÈ rvi et al, 1999), and energy resulting in similar cellular response based on morphology of the cells and preliminary experiments were selected for UVB (data not shown). The e ect of UV-radiation on cell cycle and apoptosis was studied by DNA replication assays based on 5-BrdU incorporation and by¯ow cytometry.…”

Section: Uv-radiation Elicits Different Dose-dependent Cellular Respomentioning

confidence: 99%

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UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts

Taya²,

2001

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We address here the e ects of increasing¯uencies of UV-radiation on stability, modi®cations, activity and HDM2-interactions of endogenous p53 tumor suppressor and on cellular damage response of human diploid ®broblasts. Low amounts of UVB/C-radiation induced a transient cell cycle arrest of the cells which correlated with rapid but transient increase in p53 levels. In contrast, high UV-¯uency caused cell apoptosis and a slower but sustained increase in p53. Regulation of p53 target genes was highly dependent on the radiation dose used. Whereas low doses induced p21/Cip1/Waf1 and HDM2, high doses induced only GADD45 and BAX increasing the BAX:BCL-2 ratio. The levels of HDM2, a negative regulator of p53, increased only by the low dose of UVC and p53-HDM2 association was promoted. In the absence of HDM2-induction after the high dose of UV-radiation p53-HDM2-interaction was promoted, but HDM2 failed to downregulate p53. p53 site-speci®c modi®cations (Ser15, Ser33, Ser37, Lys382) varied kinetically and were dependent on the¯uency of the radiation used. Maximal phosphorylation of p53 on Ser15 and Ser33 correlated with increased levels of HDM2-free p53. The results suggest that regulation of p53 and HDM2 by UV-radiation is highly dosedependent and contributes to the outcome of the cellular response. Oncogene (2001) 20, 6784 ± 6793.

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Section: Discussionmentioning

confidence: 97%

Section: Uv-radiation Elicits Different Dose-dependent Cellular Respomentioning

confidence: 99%

UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts

Taya²,

2001

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“…Data shown here are representative of at least three independent experiments. p16-silencing augments apoptosis in cervical cancer WM Lau et al In the absence of DNA damage, we found that p16-silenced cells had elevated levels of Rb, p53 and p21 protein, but did not undergo growth arrest or apoptosis that is commonly associated with p53 and p21 upregulation (el-Deiry et al, 1994;Haapajarvi et al, 1999). This could be owing to the effects of E6 and E7, both of which cooperate to bypass p53-induced G1 arrest and subsequently drive cell-cycle progression in cervical cancer cells (Hawley-Nelson et al, 1989;Demers et al, 1994;Jones and Munger, 1997).…”

Section: Discussionmentioning

confidence: 74%

p16INK4A-silencing augments DNA damage-induced apoptosis in cervical cancer cells

Lau

Hui

2007

Oncogene

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“…For example, a subset of known p53 target genes was induced at least to some extent upon CP-31398 treatment in HCT116-p53 Ϫ/Ϫ colon carcinoma cells as well as in HCT116-p53 ϩ/ϩ cells (14,16). Notably, p53-independent activation of many classical p53 target genes has been observed in other systems as well, including UV irradiation (31,32). The mechanisms responsible for these parallel, yet overlapping pathways of gene regulation remain unclear.…”

Section: Discussionmentioning

confidence: 99%

The Wilms Tumor Suppressor-1 Target Gene Podocalyxin Is Transcriptionally Repressed by p53

Stanhope-Baker¹,

Kessler²,

et al. 2004

Journal of Biological Chemistry

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Wilms tumor is a pediatric kidney cancer that affects 1 in 10,000 children. The Wilms tumor suppressor-1 (WT1) 1 gene was identified as a tumor suppressor gene based upon the presence of WT1 mutations in a subset (ϳ10 -15%) of Wilms tumor samples (reviewed in Ref. 1). However, the majority of Wilms tumor cases cannot be explained by genetic alteration of the WT1 locus. There may be disruption of biological pathways either upstream or downstream of WT1, or there may be pathways independent of WT1 leading to this type of neoplasm. Several lines of evidence suggest that p53 also plays an important role in the development and/or progression of Wilms tumors. The p53 and WT1 tumor suppressor genes encode transcription factors that have been shown to interact physically and to modulate each other's function in some experimental situations (2). p53 can alter the transcription regulatory activity of WT1. In addition, WT1 stabilizes the p53 protein, alters its activity as a transcription factor, and prevents p53-induced apoptosis (2, 3). Physical and functional interaction has also been observed between the p53 family members p73 and p63 and WT1 (4). Further evidence for biologically relevant interaction between WT1 and p53 includes the fact that the majority of Wilms tumors develop in the presence of wild-type p53 (5). This is in contrast to adult onset human tumors, in which p53 mutations are frequently observed (ϳ50%). The small subset of Wilms tumors that do harbor p53 mutations develop into much more aggressive anaplastic tumors (between 3 and 7% of the total) that are characterized by unfavorable histology, increased metastasis, chemoresistance, and poor prognosis (6 -9). Moreover, Li-Fraumeni patients carrying germ-line p53 mutations are predisposed to development of Wilms tumors (10), and Wilms tumors are one of a small number of cancers that are specifically associated with such mutations (11). To better understand the involvement of both p53 and WT1 in pathways leading to Wilms tumorigenesis, we have used cDNA microarrays to profile gene expression changes dependent upon the activity of these two factors.To accomplish this, we developed strategies to alter the function of WT1 and p53 in a Wilms tumor cell line, WiT49. This cell line is characteristic of anaplastic Wilms tumors in that it expresses wild-type WT1 and mutant p53. We have previously shown that WT1 activity can be effectively abrogated in WiT49 cells by expression of a naturally occurring dominant-negative mutant version of the protein (DDS5) (12). To restore wild-type p53 function in WiT49 cells, we made use of the small molecule compound CP-31398 developed by Pfizer. CP-31398 was originally shown to stabilize the p53 protein with mutation at codon 173, 175, 249, or 273 in the wild-type conformation and to allow its transcriptional and tumor suppressor functions (13). More recently, it has been shown that CP-31398 can stabilize the wild-type p53 protein as well (14 -16). We found here that CP-31398 restores activity to the codon 248 mutant p53 prese...

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UV Radiation Is a Transcriptional Inducer of p21Cip1/Waf1Cyclin-Kinase Inhibitor in a p53-Independent Manner

Cited by 52 publications

References 39 publications

UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts

UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts

p16INK4A-silencing augments DNA damage-induced apoptosis in cervical cancer cells

The Wilms Tumor Suppressor-1 Target Gene Podocalyxin Is Transcriptionally Repressed by p53

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