UV irradiation leads to transient changes in phosphorylation and stability of tumor suppressor protein p53

Scheidtmann, Karl Heinz; Landsberg, G

doi:10.3892/ijo.9.6.1277

Cited by 2 publications

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“…The altered p53 regulation observed in IRF-1-deficient hepatocytes might reflect changes in the p53 phosphorylation state (24)(25)(26)(27). Such a change could explain the increased basal p53 reporter activity observed without a commensurately increased propor- tion of p53 immunoreactive hepatocytes.…”

Section: Discussionmentioning

confidence: 99%

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Altered DNA repair and dysregulation of p53 in IRF‐1 null hepatocytes

Prost¹,

Bellamy²,

Cunningham³

et al. 1998

FASEB j.

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The tumor suppressor proteins IRF-1 and p53 are involved in response pathways after DNA damage. In different cell types, IRF-1 and p53 can cooperate to produce cell cycle arrest (embryo fibroblasts) or can independently trigger apoptosis (lymphoid cells). p53 may also regulate DNA repair, but there is no information on IRF-1 and repair. The cell lineage dependency of these effects precludes extrapolation of findings to other tissues of relevance to human cancer. Here, we report the consequences of IRF-1 deficiency for apoptosis, cell cycle arrest, and DNA repair in primary hepatocytes after DNA damage and extend previous work on the role of p53 in hepatocytes. IRF-1-deficient hepatocytes showed reduced DNA repair activity compared with wild-type, as assessed by unscheduled DNA synthesis after UV irradiation (10J/m2) and by host reactivation of a UV-damaged reporter construct. p53-deficient hepatocytes also showed reduced unscheduled DNA synthesis after UV, but there was no impairment of specific repair in host reactivation assays. IRF-1 deficiency did not affect the p53-dependent G1/S arrest after UV irradiation. Hepatocyte apoptosis after UV treatment, previously reported to be independent of p53, was also independent of IRF-1. However, IRF-1 deficiency produced dysregulation of p53, manifested as increased transactivation of a p53-reporter plasmid in undamaged hepatocytes, and accelerated p53 stabilization after DNA damage. Hence, in hepatocytes, IRF-1 is not required for growth arrest or apoptosis after DNA damage, but the results suggest for the first time a role in DNA repair regulation.

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Section: Discussionmentioning

confidence: 99%

“…Twenty-four hours after plating, hepatocyte monolayers were irradiated with 0, 15, or 50 J/m 2 , and at various times after treatment (24,48,72,96, 120 h) fixed in acid methanol/formalin. After Feulgen staining and a light green counterstain, apoptotic cells were counted under light microscopy.…”

Section: Evaluation Of Apoptosismentioning

confidence: 99%

Altered DNA repair and dysregulation of p53 in IRF‐1 null hepatocytes

Prost¹,

Bellamy²,

Cunningham³

et al. 1998

FASEB j.

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Mukhopadhyay

Roth²,

Acosta³

et al. 1998

Apoptosis

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The natural metabolic byproduct of estradiol, 2-methoxyestradiol (2-MeOE2), induces apoptosis in human lung cancer cells by a p53-dependent mechanism. The expression of wild-type p53 isoforms was investigated in H1299 non-small cell lung carcinoma cells induced into apoptosis by 2-MeOE2. H1299 cells lack endogenous p53 and undergo predominantly a G1 arrest when infected with a recombinant wild-type p53 adenovirus. However, when H1299 cells transfected with p53 were treated with 2-MeOE2, they underwent rapid and extensive apoptosis. H1299 cells expressing mutant his273 p53 were unaffected by 2-MeOE2, indicating a dependence of 2-MeOE2-mediated apoptosis on the presence of a functional p53. Analysis of wild-type p53 phosphoisoforms in H1299 cells by two-dimensional gel electrophoresis revealed that 2-MeOE2 induced a unique group of acidic p53 isoforms. Although most of the wild-type p53 in untreated H1299 cells migrated as at least five diffuse species with isoelectric points from pH 5.5-6.3, as many as nine additional forms migrating toward the acidic region with pI values from 4.4-5.3 were detected in 2-MeOE2-treated apoptotic cells. Two other agents known to induce apoptosis, vinblastine and actinomycin D, induced a similar pattern of acidic p53 species as that observed for 2-MeOE2. The results indicated that the induction of apoptosis in H1299 cells by 2-MeOE2 is dependent on the upregulation of specific p53 isoforms. Identification of the specific p53 phosphoisoforms induced by MeOE2 will be an important step in understanding the regulation and function of p53 in apoptosis.

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UV irradiation leads to transient changes in phosphorylation and stability of tumor suppressor protein p53

Cited by 2 publications

References 0 publications

Altered DNA repair and dysregulation of p53 in IRF‐1 null hepatocytes

Altered DNA repair and dysregulation of p53 in IRF‐1 null hepatocytes

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