title: Rapamycin prevents strong phosphorylation of p53 on serine 46 and attenuates activation of the p53 pathway in A549 lung cancer cells exposed to actinomycin D.
abstract: The activation of the p53 pathway by 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), a molecule that mimics metabolic stress, is attenuated by rapamycin, an inhibitor of mTOR kinase, immunosuppressant, and cancer drug. Rapamycin also extends lifespan in experimental animals. Because AICAR is a relatively weak activator of p53, we investigated whether stimulation of p53 by the strong activator actinomycin D is also sensitive to the inhibitory effect of rapamycin. In A549 lung cancer cells, activation of p53 by actinomycin D was associated with phosphorylation of p53 on Ser46. Rapamycin inhibited the accumulation of phospho-Ser46 p53, attenuated upregulation of some p53 target genes, and altered cell-cycle progression. Moreover, in cells exposed to actinomycin D, rapamycin attenuated the accumulation of PML, a protein that in some conditions stimulates Ser46 phosphorylation. However, Ser46 phosphorylation was not diminished in PML-knockdown cells, suggesting that in our system PML does not play a major role in stimulating p53 phosphorylation on Ser46. Knockdown of p53 diminished the upregulation of PML by stress-inducing agents, consistent with the idea that PML is a p53-regulated gene. Our data suggest that the attenuation of p53 phosphorylation on Ser46 may play a significant role in the biological activity of anti-aging rapamycin.
authors.affiliation: Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska - Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland.
authors.forename: Małgorzata
authors.initials: M
authors.lastname: Krześniak
authors.affiliation: Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska - Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland.
authors.forename: Artur
authors.initials: A
authors.lastname: Zajkowicz
authors.affiliation: Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska - Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland.
authors.forename: Iwona
authors.initials: I
authors.lastname: Matuszczyk
authors.affiliation: Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska - Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-101 Gliwice, Poland. Electronic address: rusinm@rocketmail.com.
authors.forename: Marek
authors.initials: M
authors.lastname: Rusin
mesh_terms: D000375:Aging / Q000187:drug effects / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003609:Dactinomycin / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000071156:Promyelocytic Leukemia Protein; D012694:Serine; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; C495901:TP53 protein, human; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; D003609:Dactinomycin; D012694:Serine; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: Actinomycin D; Phosphorylation; Rapamycin; Survivin; p53