Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The murine homologue of the ATF3 transcription factor increases tumor metastases but, surprisingly, represses 72-kDa type IV metalloproteinase (MMP-2) expression. The current study describes a novel mechanism by which ATF3 regulates transcription. Progressive deletions of the MMP-2 promoter indicated a 38-base pair region (-1659/-1622) necessary for the ATF3-mediated repression. This region lacked CREB/AP-1 motifs but contained a consensus p53 motif shown previously to regulate MMP-2 expression. The activity of a p53 response element-driven luciferase reporter was reduced in ATF3-expressing HT1080 clones. Although MMP-2 promoter activity was not repressed by ATF3 in p53-deficient Saos-2 cells, p53 re-expression increased MMP-2 promoter activity and restored the sensitivity to ATF3. The activity of a GAL4-driven reporter in HT1080 cells co-expressing the full-length p53 sequence fused to the GAL4 DNA binding domain was diminished by ATF3. p53-ATF3 protein-protein interactions were demonstrated both in vivo and in vitro. Cell cycle analysis, performed as an independent assay of p53 function, revealed that gamma-irradiation-induced slowed G(2)/M cell cycle progression (attributable to p53) was countered by ATF3. Thus, ATF3 represses MMP-2 expression by decreasing the trans-activation of this gene by p53.
 ...
PMID:ATF3 represses 72-kDa type IV collagenase (MMP-2) expression by antagonizing p53-dependent trans-activation of the collagenase promoter. 1179 11

Activating transcription factor 3 (ATF3) is an immediate early response gene that is induced in cells exposed to a variety of stress stimuli. In this report, upon exposure of cells to ultraviolet (UV) or proteasome inhibitor MG132, ATF3 protein was induced more efficiently in cells with intact p53 allele than in those with null mutant p53 allele. In Saos-2 cells harboring the temperature-sensitive mutant p53(Val-138), the expression of ATF3 gene was more significant at permissive temperature of 32.5 degrees C than at non-permissive 37.5 degrees C. Reporter assay of the human ATF3 gene promoter identified two p53-responsive elements at -379 to -370 and -351 to -342 from the transcriptional start site. These elements were capable of conferring p53 responsiveness to a heterologous promoter and specifically bound p53 protein in electrophoretic mobility shift assay. Furthermore, ATF3 gene promoter was more significantly activated by UV in cells with wild p53 allele. These results clearly show that the human ATF3 gene is one of the target genes directly activated by p53 and may suggest a functional link between stress-inducible transcriptional repressor ATF3 and p53.
 ...
PMID:Transcriptional activation of the human stress-inducible transcriptional repressor ATF3 gene promoter by p53. 1237 30

Mammalian cells have a remarkable diverse repertoire of response to genotoxic stress that damage DNA. Cellular responses to DNA damaging agents will initially exhibit gene induction, which is regulated by complex mechanism(s) and probably involves multiple signaling pathways. In this paper, we demonstrate that induction of ATF3 protein, a member of the ATF/CREB family of transcription factors, by ionizing radiation (IR) requires normal cellular p53 function. In contrast, induction of ATF3 after UV radiation (UV) or Methyl methanesulphonate (MMS) is independent of p53 status. Induction of ATF3 by DNA damage is rapid, transient, and through a transcriptional mechanism. The ATF3 promoter is induced by UV and MMS, but not by IR. In addition, ATF3 promoter can be activated by MEKK1, an upstream activator of the ERK and JNK kinase pathway, but not induced following p53 expression. Those results indicate that regulation of ATF3 induction after DNA damage utilizes both the p53-dependent and -independent pathways, and may also involve MAP kinase signaling pathways. Using the tetracycline-inducible system (tet-off), we have found that over-expression of ATF3 protein moderately suppresses cell growth. Interestingly, over-expression of ATF3 protein is able to slow down progression of cells from G1 to S phase, indicating that ATF3 protein might play a negative role in the control of cell cycle progression.
 ...
PMID:ATF3 induction following DNA damage is regulated by distinct signaling pathways and over-expression of ATF3 protein suppresses cells growth. 1238 11

Activating transcription factor 3 (ATF3) is rapidly induced by diverse environmental insults including genotoxic stress. We report herein that its interaction with p53, enhanced by genotoxic stress, stabilizes the tumor suppressor thereby augmenting functions of the latter. Overexpression of ATF3 (but not a mutated ATF3 protein (Delta102-139) devoid of its p53-binding region) prevents p53 from MDM2-mediated degradation and leads to increased transcription from p53-regulated promoters. ATF3, but not the Delta102-139 protein, binds the p53 carboxy-terminus and diminishes its ubiquitination and nuclear export. Genotoxic-stressed ATF3-null mouse embryonic fibroblasts, or cells in which ATF3 was reduced by small interference RNA, show inefficient p53 induction and impaired apoptosis compared with wild-type cells. ATF3-null cells (but not wild-type cells), which poorly accumulate p53, are transformed by oncogenic Ras. Thus, ATF3 is a novel stress-activated regulator of p53 protein stability/function providing the cell with a means of responding to a wide range of environmental insult, thus maintaining DNA integrity and protecting against cell transformation.
 ...
PMID:Activating transcription factor 3, a stress sensor, activates p53 by blocking its ubiquitination. 1593 12

ATF3 is a highly conserved eukaryotic transcription factor that is ubiquitously upregulated transcriptionally during cellular responses to a variety of stresses, in particular DNA damage. However, the role of ATF3 in the DNA damage response is unclear. Transgenic mice that overexpress human ATF3 in basal epithelial cells under the control of the bovine keratin 5 (K5) promoter were constructed and characterized for epidermal alterations. Strong, nuclear expression of the exogenous ATF3 protein was seen in basal cells of the epidermis, hair follicles, and oral mucosa. Hyperplastic changes in the K5-expressing, outer root sheath (ORS) cells of the hair follicle were observed in young mice, resulting in multiple layers of ORS cells in the mature follicle and large aberrantly shaped follicles. Mild hyperplasia of the interfollicular epidermis was also noted, increasing with age. However, no epidermal tumors were identified in BK5.ATF3 mice observed for 16 mo. At 16 mo of age, most transgenic mice exhibited multi-focal areas of hyperplasia and dysplasia in the oral mucosa, with cellular atypia and underlying acute inflammatory changes. Neoplastic lesions were also seen in the oral cavity of BK5.ATF3 mice, including oral squamous cell carcinoma (60% incidence) and basal cell tumors with follicular differentiation (70% incidence), but not in non-transgenic FVB/N littermates. Heterogeneous nuclear expression (or stabilization) of p53 protein was seen in some oral dysplasias, with a patchy distribution primarily in the least differentiated layers of the lesions. This represents the first indication that ATF3 may have oncogenic properties in epithelial cells.
 ...
PMID:Epidermal hyperplasia and oral carcinoma in mice overexpressing the transcription factor ATF3 in basal epithelial cells. 1729 36