title: Role and interaction of p53, BAX and the stress-activated protein kinases p38 and JNK in benzo(a)pyrene-diolepoxide induced apoptosis in human colon carcinoma cells.
abstract: Polycyclic aromatic hydrocarbons are ubiquitous environmental pollutants formed during incomplete combustion of organic material. For example benzo[a]pyrene (B[a]P) is a constituent and contaminant of cigarette smoke, automobile exhaust, industrial waste and even food products. B[a]P is carcinogenic to rodents and humans. B[a]P induces its own metabolism, which generates different metabolites such as the highly reactive electrophilic genotoxin and ultimal carcinogen B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE can bind to nucleophilic macromolecules such as proteins and DNA and causes mutations. Multiple defence mechanisms have evolved to protect the cell from DNA damage. Specific signalling pathways operate to detect and repair different kinds of lesions. In case, the damage is poorly removed expansion of damaged cells can be counteracted, e.g., by the inhibition of proliferation or triggering apoptosis. Examples of damage sensors and transducers are stress-activated protein kinases (SAPKs) and the tumour suppressor protein p53. Here, we studied the role of p53 and the pro-apoptotic protein BAX in BPDE-induced cell death by using wild-type- or knock-out-human colon carcinoma cells. As reported previously, we could reconfirm a critical role of p53 in BPDE-induced apoptosis. Furthermore, induced levels of total p53 and its transcriptional target p21 declined at higher BPDE concentrations correlating with reduced rates of apoptosis. Interestingly, increased phosphorylation of p53 at serine 15 remained elevated at higher BPDE concentrations thus disconnecting p53 phosphorylation from downstream apoptosis. Hence, phosphorylation of p53 seems not only to be a more sensitive biomarker of BPDE exposure but might serve other functions unrelated to apoptosis. In addition, we identify BAX as a novel and essential factor to trigger the intrinsic pathway of apoptosis in response to BPDE. Furthermore, BPDE in parallel activates the SAPKs p38 and JNK, which are as well involved in apoptosis. Although several routes of mutual regulation of p53 and SAPK have been described, we present evidence that the SAPK pathway in response to genotoxic stress can unexpectedly operate independently of p53 and controls apoptosis by a novel mechanism possibly downstream of caspases.
authors: Karlsruhe Institute of Technology, Campus North, Institute of Toxicology and Genetics, Hermann-von-Helmholtz-Platz 1, 76344, Eggenstein-Leopoldshafen, Germany.
authors: Julia
authors: J
authors: Donauer
authors: Ilona
authors: I
authors: Schreck
authors: Urban
authors: U
authors: Liebel
authors: Carsten
authors: C
authors: Weiss
mesh_terms: D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D004785:Environmental Pollutants / Q000633:toxicity; D045325:HCT116 Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D009152:Mutagenicity Tests; D011084:Polycyclic Aromatic Hydrocarbons / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C494826:BAX protein, human; D004785:Environmental Pollutants; D011084:Polycyclic Aromatic Hydrocarbons; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4