Genotoxic stress induces coordinately regulated alternative splicing of the p53 modulators MDM2 and MDM4

• Published in: Cancer research (Chicago, Ill.) Vol. 66; no. 19; pp. 9502 - 9508
• Main Authors: CHANDLER, Dawn S, SINGH, Ravi K, CALDWELL, Lisa C, BITLER, Jaquelyn L, LOZANO, Guillermina
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.10.2006
• Subjects: Alternative Splicing - genetics; Alternative Splicing - radiation effects; Animals; Antineoplastic agents; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Caffeine - pharmacology; Cell Cycle Proteins - antagonists & inhibitors; Cell Line, Tumor - drug effects; Cell Line, Tumor - metabolism; Cell Line, Tumor - radiation effects; Cisplatin - toxicity; DNA Damage; DNA Modification Methylases - genetics; DNA Repair Enzymes - genetics; DNA, Neoplasm - drug effects; DNA, Neoplasm - radiation effects; DNA-Binding Proteins - antagonists & inhibitors; Genes, p53; Humans; Medical sciences; Mice; Nuclear Proteins - genetics; Nuclear Proteins - physiology; Pharmacology. Drug treatments; Protein Isoforms - genetics; Protein Isoforms - physiology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Proto-Oncogene Proteins c-mdm2 - genetics; Proto-Oncogene Proteins c-mdm2 - physiology; Recombinant Fusion Proteins - physiology; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - genetics; Tumors; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - physiology; Ultraviolet Rays; Alternative splicing; Modulator; TP53 Gene; Toxicity; C-Onc gene; Genotoxicity; mdm2 Gene; Protooncogene; Stress; Tumor suppressor gene
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-05-4271

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.