ASPP2 suppresses squamous cell carcinoma via ReIA/p65–mediated repression of p63

Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene delection. Here we report a haploinsufficient SCC mouse model in which...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (44), p.17969-17974
Main Authors: Tordella, Luca, Koch, Sofia, Salter, Victoria, Pagotto, Anna, Doondeea, Jessica B., Feller, Stephan M., Ratnayaka, Indrika, Zhong, Shan, Goldin, Robert D., Lozano, Guillermina, McKeon, Frank D., Tavassoli, Mahvash, Fritzsche, Florian, Huber, Gerhard F., Rössle, Matthias, Moch, Holger, Lu, Xin
Format: Article
Language:English
Subjects:
Carcinoma
Cell lines
Cell nucleus
Epithelial cells
Genetic mutation
Keratinocytes
Lymphoma
Skin
Squamous cell carcinoma
Tumors
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Summary:Squamous cell carcinoma (SCC) is highly malignant and refractory to therapy. The majority of existing mouse SCC models involve multiple gene mutations. Very few mouse models of spontaneous SCC have been generated by a single gene delection. Here we report a haploinsufficient SCC mouse model in which exon 3 of the Tp53BP2 gene (a p53 binding protein) was deleted in one allele in a BALB/c genetic background. Tp53BP2 encodes ASPP2 (ankyrin repeats, SH3 domain and protein rich region containing protein 2). Keratinocyte differentiation induces ASPP2 and its expression is inversely correlated with p63 protein in vitro and in vivo. Upregulation of p63 expression is required for ASPP2 Δexon3/+ BALB/c mice to develop SCC, as heterozygosity of p63 but not p53 prevents them from developing it. Mechanistically, ASPP2 inhibits ΔNp63 expression through its ability to bind IκB and enhance nuclear ReI/A p65, a component of the NF-κB transcription complex, which mediates the repression of p63. Reduced ASPP2 expression associates with tumor metastasis and increased p63 expression in human head and neck SCCs. This study identifies ASPP2 as a tumor suppressor that suppresses SCC via inflammatory signaling through NF-κB–mediated repression of p63.
ISSN:0027-8424