ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63

Luca Tordella; Sofia Koch; Victoria Salter; Anna Pagotto; Jessica B Doondeea; Stephan M Feller; Indrika Ratnayaka; Shan Zhong; Robert D Goldin; Guillermina Lozano; Frank D McKeon; Mahvash Tavassoli; Florian Fritzsche; Gerhard F Huber; Matthias Rössle; Holger Moch; Xin Lu

doi:10.1073/pnas.1309362110

ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63

Luca Tordella, Sofia Koch, Victoria Salter, Anna Pagotto, Jessica B Doondeea, Stephan M Feller, Indrika Ratnayaka, Shan Zhong, Robert D Goldin, Guillermina Lozano, Frank D McKeon, Mahvash Tavassoli, Florian Fritzsche, Gerhard F Huber, Matthias Rössle, Holger Moch, Xin Lu

Centre for Host Microbiome Interactions

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

Abstract

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 deletion. 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. Up-regulation 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 Rel/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.

Original language	English
Pages (from-to)	17969-17974
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	44
DOIs	https://doi.org/10.1073/pnas.1309362110
Publication status	Published - 29 Oct 2013

Keywords

Animals
Carcinoma, Squamous Cell
Cell Line
Crosses, Genetic
DNA Primers
Disease Models, Animal
Haploinsufficiency
Humans
Immunoblotting
Immunoprecipitation
Mice
Mice, Inbred BALB C
Microarray Analysis
Phosphoproteins
RNA, Small Interfering
Real-Time Polymerase Chain Reaction
Signal Transduction
Trans-Activators
Transcription Factor RelA
Tumor Suppressor Proteins

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10.1073/pnas.1309362110

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Tordella, L., Koch, S., Salter, V., Pagotto, A., Doondeea, J. B., Feller, S. M., Ratnayaka, I., Zhong, S., Goldin, R. D., Lozano, G., McKeon, F. D., Tavassoli, M., Fritzsche, F., Huber, G. F., Rössle, M., Moch, H., & Lu, X. (2013). ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63. Proceedings of the National Academy of Sciences of the United States of America, 110(44), 17969-17974. https://doi.org/10.1073/pnas.1309362110

@article{ebee5f7705bb4efa82609ba8b1b0be38,

title = "ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63",

abstract = "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 deletion. 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. Up-regulation 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 Rel/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.",

keywords = "Animals, Carcinoma, Squamous Cell, Cell Line, Crosses, Genetic, DNA Primers, Disease Models, Animal, Haploinsufficiency, Humans, Immunoblotting, Immunoprecipitation, Mice, Mice, Inbred BALB C, Microarray Analysis, Phosphoproteins, RNA, Small Interfering, Real-Time Polymerase Chain Reaction, Signal Transduction, Trans-Activators, Transcription Factor RelA, Tumor Suppressor Proteins",

author = "Luca Tordella and Sofia Koch and Victoria Salter and Anna Pagotto and Doondeea, {Jessica B} and Feller, {Stephan M} and Indrika Ratnayaka and Shan Zhong and Goldin, {Robert D} and Guillermina Lozano and McKeon, {Frank D} and Mahvash Tavassoli and Florian Fritzsche and Huber, {Gerhard F} and Matthias R{\"o}ssle and Holger Moch and Xin Lu",

year = "2013",

month = oct,

day = "29",

doi = "10.1073/pnas.1309362110",

language = "English",

volume = "110",

pages = "17969--17974",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Acad Sciences",

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Tordella, L, Koch, S, Salter, V, Pagotto, A, Doondeea, JB, Feller, SM, Ratnayaka, I, Zhong, S, Goldin, RD, Lozano, G, McKeon, FD, Tavassoli, M, Fritzsche, F, Huber, GF, Rössle, M, Moch, H & Lu, X 2013, 'ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63', Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 44, pp. 17969-17974. https://doi.org/10.1073/pnas.1309362110

TY - JOUR

T1 - ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63

AU - Tordella, Luca

AU - Koch, Sofia

AU - Salter, Victoria

AU - Pagotto, Anna

AU - Doondeea, Jessica B

AU - Feller, Stephan M

AU - Ratnayaka, Indrika

AU - Zhong, Shan

AU - Goldin, Robert D

AU - Lozano, Guillermina

AU - McKeon, Frank D

AU - Tavassoli, Mahvash

AU - Fritzsche, Florian

AU - Huber, Gerhard F

AU - Rössle, Matthias

AU - Moch, Holger

AU - Lu, Xin

PY - 2013/10/29

Y1 - 2013/10/29

N2 - 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 deletion. 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. Up-regulation 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 Rel/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.

AB - 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 deletion. 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. Up-regulation 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 Rel/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.

KW - Animals

KW - Carcinoma, Squamous Cell

KW - Cell Line

KW - Crosses, Genetic

KW - DNA Primers

KW - Disease Models, Animal

KW - Haploinsufficiency

KW - Humans

KW - Immunoblotting

KW - Immunoprecipitation

KW - Mice

KW - Mice, Inbred BALB C

KW - Microarray Analysis

KW - Phosphoproteins

KW - RNA, Small Interfering

KW - Real-Time Polymerase Chain Reaction

KW - Signal Transduction

KW - Trans-Activators

KW - Transcription Factor RelA

KW - Tumor Suppressor Proteins

U2 - 10.1073/pnas.1309362110

DO - 10.1073/pnas.1309362110

M3 - Article

C2 - 24127607

SN - 0027-8424

VL - 110

SP - 17969

EP - 17974

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 44

ER -

ASPP2 suppresses squamous cell carcinoma via RelA/p65-mediated repression of p63

Abstract

Keywords

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