The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression

Alessandro Torgovnick; Jan Michel Heger; Vasiliki Liaki; Jörg Isensee; Anna Schmitt; Gero Knittel; Arina Riabinska; Filippo Beleggia; Lucie Laurien; Uschi Leeser; Christian Jüngst; Florian Siedek; Wenzel Vogel; Niklas Klümper; Hendrik Nolte; Maike Wittersheim; Lars Tharun; Roberta Castiglione; Marcus Krüger; Astrid Schauss; Sven Perner; Manolis Pasparakis; Reinhard Büttner; Thorsten Persigehl; Tim Hucho; Grit Sophie Herter-Sprie; Björn Schumacher; Hans Christian Reinhardt

doi:10.1016/j.celrep.2018.09.079

The Cdkn1a^SUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression

Alessandro Torgovnick^*, Jan Michel Heger, Vasiliki Liaki, Jörg Isensee, Anna Schmitt, Gero Knittel, Arina Riabinska, Filippo Beleggia, Lucie Laurien, Uschi Leeser, Christian Jüngst, Florian Siedek, Wenzel Vogel, Niklas Klümper, Hendrik Nolte, Maike Wittersheim, Lars Tharun, Roberta Castiglione, Marcus Krüger, Astrid SchaussSven Perner, Manolis Pasparakis, Reinhard Büttner, Thorsten Persigehl, Tim Hucho, Grit Sophie Herter-Sprie, Björn Schumacher, Hans Christian Reinhardt

^*Corresponding author for this work

Institute of Pathology

2 Citations (Scopus)

Abstract

Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1a^SUPER mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1a^SUPER mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53^SUPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1a^SUPER allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression. Torgovnick et al. create a mouse model, carrying a third copy of Cdkn1a (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The Cdkn1a^SUPER animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression.

Original language	English
Journal	Cell Reports
Volume	25
Issue number	4
Pages (from-to)	1027-1039.e6
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2018.09.079
Publication status	Published - 23.10.2018

Funding

We are indebted to M. Serrano (Institute for Research in Biomedicine; Barcelona) for providing cell lines derived from 3MC-induced sarcomas. M. van Vugt (Utrecht Medical Center) provided the GFP:53BP1 construct. We thank A. Florin and U. Rommerscheidt-Fuß from the Institute of Pathology, University Hospital Cologne, for their outstanding technical support. This work was supported by the Deutsche Forschungsgemeinschaft ( KFO-286/RP2 , RE 2246/2-1 , RE 2246/7-1 CECAD , SFB-829 to H.C.R., CECAD , SFB-829 , SFB-670 , KFO-286/RP1 , KFO-329 to B.S. and HE 6897/1-1 to G.S.H.-S.), the German federal state North Rhine Westphalia (NRW) as part of the EFRE initiative (grant LS-1-1-030a , H.C.R.), the Else Kröner-Fresenius Stiftung ( EKFS-2014-A06 , H.C.R.), the European Commission (ERC Starting grant 260383 and the FP7 Marie Curie Actions ITN CodeAge 316354 , ITN aDDRess 316390 , ITN MARRIAGE 316964 , and the Flag-Era-JTC2015 GRAPHENE to B.S.), the Deutsche Krebshilfe ( 111724 , H.C.R., 70112899 to B.S.), the Bundesministerium für Forschung und Bildung (Sybacol FKZ0315893 ) and the Koeln Fortune Program/Faculty of Medicine, University of Cologne ( 38/2010 to G.S.H.-S.). The results are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/ .

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10.1016/j.celrep.2018.09.079

Cite this

Torgovnick, A., Heger, J. M., Liaki, V., Isensee, J., Schmitt, A., Knittel, G., Riabinska, A., Beleggia, F., Laurien, L., Leeser, U., Jüngst, C., Siedek, F., Vogel, W., Klümper, N., Nolte, H., Wittersheim, M., Tharun, L., Castiglione, R., Krüger, M., ... Reinhardt, H. C. (2018). The Cdkn1a^SUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression. Cell Reports, 25(4), 1027-1039.e6. https://doi.org/10.1016/j.celrep.2018.09.079

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title = "The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression",

abstract = "Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPER mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1aSUPER mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPER allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression. Torgovnick et al. create a mouse model, carrying a third copy of Cdkn1a (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The Cdkn1aSUPER animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression.",

author = "Alessandro Torgovnick and Heger, \{Jan Michel\} and Vasiliki Liaki and J{\"o}rg Isensee and Anna Schmitt and Gero Knittel and Arina Riabinska and Filippo Beleggia and Lucie Laurien and Uschi Leeser and Christian J{\"u}ngst and Florian Siedek and Wenzel Vogel and Niklas Kl{\"u}mper and Hendrik Nolte and Maike Wittersheim and Lars Tharun and Roberta Castiglione and Marcus Kr{\"u}ger and Astrid Schauss and Sven Perner and Manolis Pasparakis and Reinhard B{\"u}ttner and Thorsten Persigehl and Tim Hucho and Herter-Sprie, \{Grit Sophie\} and Bj{\"o}rn Schumacher and Reinhardt, \{Hans Christian\}",

year = "2018",

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doi = "10.1016/j.celrep.2018.09.079",

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Torgovnick, A, Heger, JM, Liaki, V, Isensee, J, Schmitt, A, Knittel, G, Riabinska, A, Beleggia, F, Laurien, L, Leeser, U, Jüngst, C, Siedek, F, Vogel, W, Klümper, N, Nolte, H, Wittersheim, M, Tharun, L, Castiglione, R, Krüger, M, Schauss, A, Perner, S, Pasparakis, M, Büttner, R, Persigehl, T, Hucho, T, Herter-Sprie, GS, Schumacher, B & Reinhardt, HC 2018, 'The Cdkn1a^SUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression', Cell Reports, vol. 25, no. 4, pp. 1027-1039.e6. https://doi.org/10.1016/j.celrep.2018.09.079

TY - JOUR

T1 - The Cdkn1aSUPER Mouse as a Tool to Study p53-Mediated Tumor Suppression

AU - Torgovnick, Alessandro

AU - Heger, Jan Michel

AU - Liaki, Vasiliki

AU - Isensee, Jörg

AU - Schmitt, Anna

AU - Knittel, Gero

AU - Riabinska, Arina

AU - Beleggia, Filippo

AU - Laurien, Lucie

AU - Leeser, Uschi

AU - Jüngst, Christian

AU - Siedek, Florian

AU - Vogel, Wenzel

AU - Klümper, Niklas

AU - Nolte, Hendrik

AU - Wittersheim, Maike

AU - Tharun, Lars

AU - Castiglione, Roberta

AU - Krüger, Marcus

AU - Schauss, Astrid

AU - Perner, Sven

AU - Pasparakis, Manolis

AU - Büttner, Reinhard

AU - Persigehl, Thorsten

AU - Hucho, Tim

AU - Herter-Sprie, Grit Sophie

AU - Schumacher, Björn

AU - Reinhardt, Hans Christian

PY - 2018/10/23

Y1 - 2018/10/23

N2 - Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPER mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1aSUPER mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPER allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression. Torgovnick et al. create a mouse model, carrying a third copy of Cdkn1a (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The Cdkn1aSUPER animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression.

AB - Cdkn1a, which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of Cdkn1a gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a Cdkn1aSUPER mouse, which harbors an additional Cdkn1a allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous Kras-driven lung adenocarcinoma model, we show that Cdkn1aSUPER mice display a cancer protection phenotype that is indistinguishable from that observed in Tp53SUPER animals. Moreover, we demonstrate that Tp53 and Cdkn1a cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our Cdkn1aSUPER allele enabled us to assess the contribution of Cdkn1a to Tp53-mediated tumor suppression. Torgovnick et al. create a mouse model, carrying a third copy of Cdkn1a (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The Cdkn1aSUPER animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression.

UR - https://www.scopus.com/pages/publications/85055055667

U2 - 10.1016/j.celrep.2018.09.079

DO - 10.1016/j.celrep.2018.09.079

M3 - Journal articles

C2 - 30355482

AN - SCOPUS:85055055667

SN - 2211-1247

VL - 25

SP - 1027-1039.e6

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