Phospho-ΔNp63α/NF-Y protein complex transcriptionally regulates DDIT3 expression in squamous cell carcinoma cells upon cisplatin exposure
| Autor: | Edward A. Ratovitski, Alice Y. Chuang, David Sidransky, Nanette J. Liégeois, Rose-Anne Romano, Yiping Huang, Barry Trink, Satrajit Sinha |
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| Rok vydání: | 2010 |
| Předmět: |
Programmed cell death
Transcription Genetic Down-Regulation Antineoplastic Agents Apoptosis Cell Cycle Proteins Ataxia Telangiectasia Mutated Proteins Protein Serine-Threonine Kinases Biology Downregulation and upregulation Transcriptional regulation medicine Humans Protein Interaction Domains and Motifs RNA Messenger Phosphorylation Molecular Biology Transcription factor Regulation of gene expression Cisplatin Tumor Suppressor Proteins Cell Biology medicine.disease Head and neck squamous-cell carcinoma Molecular biology Up-Regulation DNA-Binding Proteins Gene Expression Regulation Neoplastic Amino Acid Substitution CCAAT-Binding Factor Head and Neck Neoplasms Cell culture Mutation Carcinoma Squamous Cell Trans-Activators Cancer research Transcription Factor CHOP Transcription Factors Developmental Biology medicine.drug |
| Zdroj: | Cell Cycle. 9:328-338 |
| ISSN: | 1551-4005 1538-4101 |
| DOI: | 10.4161/cc.9.2.10432 |
| Popis: | Cisplatin remains the most important chemotherapeutic agent for patients with human head and neck cancer. However, tumor cells often develop resistance to cisplatin-induced apoptosis. We previously found that head and neck squamous cell carcinoma (HNSCC) cells exposed to cisplatin display a marked ATM-induced phosphorylation of DeltaNp63alpha. However, the mutated Np63-S385G failed to undergo phosphorylation by ATM kinase. We used HNSCC cell lines expressing the wild type DeltaNp63alpha or mutated DeltaNp63alpha-S385G to determine the effect of S385G mutation on the DeltaNp63alpha transcriptional activity and protein-protein interactions. The S385G mutation in DeltaNp63alpha dramatically abolished the upregulation/downregulation of downstream gene targets and the binding of DeltaNp63alpha-S385G to certain promoters. In contrast to the non-phosphorylated DeltaNp63alpha-S385G, the phospho-DeltaNp63alpha forms protein-protein complexes with NF-YA transcription factor and regulates the transcription of DDIT3 gene implicated in the programmed cell death of HNSCC cells upon cisplatin exposure. We suggest that the transcriptional activation of DeltaNp63alpha through its phosphorylation by ATM kinase in HNSCC cells exposed to cisplatin is a critical step in the subsequent sensitivity of certain human head and neck cancers to platinum therapy. |
| Databáze: | OpenAIRE |
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