Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4.
The tumor suppressor protein p53 is a transcription factor that induces G(1) arrest of the cell cycle and/or apoptosis. The murine double-minute protein MDM2 and its homologue MDM4 (also known as MDMX) are critical regulators of p53. Altered transcripts of the human homologue of mdm2, MDM2, have been identified in human tumors, such as invasive carcinoma of the breast, lung carcinoma, and liposarcoma. MDM2 alternate forms act to negatively regulate the normal MDM2 gene product, thus activating p53. Although many reports have documented a plethora of tumor types characterized by MDM2 alternative transcripts, few have investigated the signals that might initiate alternative splicing. We have identified a novel role of these alternative MDM2 transcripts in the normal surveillance mechanism of the cell and in DNA damage response. We report that alternate forms of MDM2 are detected after UV irradiation. Furthermore, we show that mouse cells treated with UV are also characterized by alternative transcripts of mdm2, suggesting that this is an important and evolutionarily conserved mechanism for regulating the expression of MDM2/mdm2. An additional p53 regulator and mdm2 family member, MDM4, is likewise alternatively spliced following UV irradiation. By activating alternative splicing of both MDM2 and MDM4, yet another layer of p53 regulation is initiated by the cells in response to damage. A stepwise model for malignant conversion by which alternate forms of MDM2 and MDM4 place selective pressure on the cells to acquire additional alterations in the p53 pathway is herein proposed.
Chandler
Dawn S
DS
Center for Childhood Cancer, Columbus Children's Research Institute and Department of Pediatrics, The Ohio State University, Columbus, OH 43205, USA. chandler@ccri.net
Singh
Ravi K
RK
Caldwell
Lisa C
LC
Bitler
Jaquelyn L
JL
Lozano
Guillermina
G
D017398:Alternative Splicing / Q000235:genetics / Q000528:radiation effects*; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002110:Caffeine / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D002945:Cisplatin / Q000633:toxicity; D004249:DNA Damage; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D004273:DNA, Neoplasm / Q000187:drug effects / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors; D016158:Genes, p53; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000502:physiology*; D014466:Ultraviolet Rays
D018797:Cell Cycle Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C482775:MDM4 protein, human; C461497:Mdm4 protein, mouse; D009687:Nuclear Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D025521:Tumor Suppressor Proteins; D002110:Caffeine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; C497206:MDM2 protein, human; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C576325:Atm protein, mouse; D017346:Protein Serine-Threonine Kinases; D045643:DNA Repair Enzymes; D002945:Cisplatin