Arsenic disrupts cellular levels of p53 and mdm2: a potential mechanism of carcinogenesis.
The antitumor protein p53 plays a critical role in DNA repair. Inorganic arsenic exposure is associated with a wide variety of human tumors, particularly of the skin. To investigate how inorganic arsenic might interfere with DNA repair and lead to greater incidence of hyperkeratosis and skin tumors, we exposed human keratinocytes (HaCaT) to environmentally relevant concentrations of arsenite for 14 days. Arsenite reduced p53 levels while concomitantly increasing the p53 regulatory protein mdm2 levels in a dose- and time-dependent manner. We propose the disruption of the p53-mdm2 loop regulating cell cycle arrest as a model for arsenic-related skin carcinogenesis and it may be important in tumors with elevated mdm2 levels.
Hamadeh
H K
HK
Department of Community and Environmental Medicine, University of California, Irvine, Irvine, California, 92697-1825, USA.
Vargas
M
M
Lee
E
E
Menzel
D B
DB
D001149:Arsenates / Q000633:toxicity; D001151:Arsenic / Q000633:toxicity*; D020261:Arsenic Poisoning; D001152:Arsenicals; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D051736:Proto-Oncogene Proteins c-mdm2; D013723:Teratogens / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000032:analysis*
D001149:Arsenates; D001152:Arsenicals; D018053:Arsenites; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D013723:Teratogens; D016159:Tumor Suppressor Protein p53; C029341:oxophenylarsine; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C015001:arsenite; D001151:Arsenic; C025657:arsenic acid