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Suppression of the mouse double minute 4 gene causes changes in cell cycle control in a human mesothelial cell line responsive to ultraviolet radiation exposure
Author(s) -
BundersonSchelvan Melisa,
Erbe Amy K.,
Schwanke Corbin,
Pershouse Mark A.
Publication year - 2009
Publication title -
environmental and molecular mutagenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1
H-Index - 87
eISSN - 1098-2280
pISSN - 0893-6692
DOI - 10.1002/em.20498
Subject(s) - cell cycle , biology , dna damage , small hairpin rna , cell growth , cell cycle checkpoint , microbiology and biotechnology , cancer research , cell , dna repair , tumor suppressor gene , mdm2 , cell culture , carcinogenesis , gene , genetics , gene knockdown , dna
The TP53 tumor suppressor gene is the most frequently inactivated gene in human cancer identified to date. However, TP53 mutations are rare in human mesotheliomas, as well as in many other types of cancer, suggesting that aberrant TP53 function may be due to alterations in its regulatory pathways. Mouse double minute 4 ( MDM4 ) has been shown to be a key regulator of TP53 activity, both independently as well as in concert with its structural homolog, Mouse Double Minute 2 ( MDM2 ). The purpose of this study was to characterize the effects of MDM4 suppression on TP53 and other proteins involved in cell cycle control before and after ultraviolet (UV) exposure in MeT5a cells, a nonmalignant human mesothelial line. Short hairpin RNA (shRNA) was used to investigate the impact of MDM4 on TP53 function and cellular transcription. Suppression of MDM4 was confirmed by Western blot. MDM4 suppressed cells were analyzed for cell cycle changes with and without exposure to UV. Changes in cell growth as well as differences in the regulation of direct transcriptional targets of TP53 , CDKN1A (cyclin‐dependent kinase 1α, p21 ) and BAX , suggest a shift from cell cycle arrest to apoptosis upon increasing UV exposure. These results demonstrate the importance of MDM4 in cell cycle regulation as well as a possible role inthe pathogenesis of mesothelioma‐type cancers. Environ. Mol. Mutagen. 2009. © 2009 Wiley‐Liss, Inc.