Guardavaccaro: Ubiquitin ligases and cancer

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The Guardavaccaro group studies the functions of the ubiquitin system in normal cells and how deregulation of this system leads to oncogenesis.

Research in our laboratory focuses on studying the molecular mechanisms through which the ubiquitin system controls cell growth and proliferation and understanding how deregulation of this network contributes to malignant transformation. We are especially interested in the role of Cullin-RING complexes, the largest class of E3 ubiquitin ligases in eukaryotes.

Key publications

USP17- and SCFβTrCP-regulated degradation of DEC1 controls the DNA damage response.

Kim J, D'Annibale S, Magliozzi R, Low TY, Jansen P, Shaltiel IA, Mohammed S, Heck AJ, Medema RJ, Guardavaccaro D

Mol Cell Biol. 34(22):4177-85


Control of Epithelial Cell Migration and Invasion by the IKKβ- and CK1α-Mediated Degradation of RAPGEF2.

Magliozzi R, Low TW, Weijts BGMW, Cheng T, Spanjaard E, Mohammed S, van Veen A, Ovaa H, de Rooij J, Zwartkruis FJT, Bos JL, de Bruin A, Heck AJR, Guardavaccaro D.

Dev Cell. 27(5):574-85.


Control of chromosome stability by the βTrCP-REST-Mad2 axis.

Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, Hernando E, Pagano M.

Nature. 452(7185):365-9.


Control of meiotic and mitotic progression by the F-box protein βTrCP1 in vivo.

Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L, Donzelli M, Margottin-Goguet F, Jackson PK, Yamasaki L, Pagano M.

Dev Cell. 4(6):799-812.


Coupled activation and degradation of eEF2K regulates protein synthesis in response to genotoxic stress.

Kruiswijk F, Yuniati L, Magliozzi R, Low TW, Lim R, Bolder R, Mohammed S, Proud CG, Heck AJR, Pagano M, and Guardavaccaro D.

Science Signaling. 5(227):ra40.


Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth.

Lasorella A, Stegmüller J, Guardavaccaro D, Liu G, Carro MS, Rothschild G, de la Torre-Ubieta L, Pagano M, Bonni A, Iavarone A.

Nature. 442(7101):471-4.


Other publications

Nodal signalling range is regulated by proprotein convertase-mediated secretion

Tessadori, F., Noël, E.S., Rens, E.G., Magliozzi, R., Evers-van Gogh, I.J.A., Guardavaccaro, D., Merks, R.M.H., Bakkers, J.

Dev Cell. Feb 11


A systems-wide screen identifies substrates of the SCFβTrCP ubiquitin ligase

Low, T.Y., Peng, M., Magliozzi, R., Mohammed, S., Guardavaccaro, D., Heck, A.J.

Science Signaling 7(356):rs8


USP17- and SCFβTrCP-regulated degradation of DEC1 controls the DNA damage response

Kim, J., D’Annibale, S., Magliozzi, R., Low, T.Y., Jansen, P., Shaltiel, I.A., Mohammed, S., Heck, A.J., Medema, R.H., Guardavaccaro, D.

Mol Cell Biol. 34(22):4177-85


J Biol Chem. 289(40):27400-9


Proteasome-dependent degradation of Transcription Factor AP4 (TFAP4) controls mitotic division

D’Annibale, S., Kim, J., Magliozzi, R., Low, T.Y., Mohammed, S., Heck, A.J., Guardavaccaro, D.

J Biol Chem 289(11):7730-7


Control of epithelial cell migration and invasion by the IKKβ- and CK1α-mediated degradation of RAPGEF2

Magliozzi, R., Low, T.W., Weijts, B.G.M.W., Cheng, T., Spanjaard, E., Mohammed, S., van Veen, A., Ovaa, H., de Rooij, J., Zwartkruis, F.J.T., Bos, J.L., de Bruin, A., Heck, A.J.R., Guardavaccaro, D.

Dev Cell 27(5):574-85


Human papillomavirus (HPV) upregulates the cellular deubiquitinase UCHL1 to suppress the keratinocyte’s innate immune response

Karim, R., Tummers, B., Meyers, C., Backendorf, C., Offringa, R., van Ommen, G.B., Melief, C.J.M., M. Boer, J, Guardavaccaro, D., van der Burg, S.H.

PLoS Pathogens 9(5)


Proteomics 13(3-4):526-3,7


Coupled activation-degradation of eEF2K regulates protein synthesis in response to genotoxic stress

Kruiswijk, F., Yuniati, L., Magliozzi, R., Low, T.W., Lim, R., Bolder, R., Mohammed, S., Proud, C.G., Heck, A.J.R., Pagano, M., Guardavaccaro, D.

Science Signaling 5(227):ra40


APC/CCdh1 controls the proteasome-mediated degradation of E2F3 during cell cycle exit

Ping, Z., Lim, R., Bashir, T., Pagano, M., Guardavaccaro, D.

Cell Cycle 11(10):1999-2005


Asb11 is a regulator of embryonic and adult regenerative myogenesis

Tee, J.M., Sartori da Silva, M., Rygiel, A., Muncan, V., Bink, R., van den Brink, G., van Tijn, P., Zivkovic, D., Kodach, L., Guardavaccaro, D., Diks, S., Peppelenbosch, M.

Stem Cells Dev 21(17):3091-103


Science Signaling 5(219):pe155


Lgr5 homologues associate with Wnt receptors and mediate R-spondin signalling

de Lau, W., Barker, N., Low, T.Y., Koo, B.K., Li, V.S., Teunissen, H., Kujala, P., Haegebarth, A., Peters, P.J., van de Wetering, M., Stange, D.E., van Es, J.E., Guardavaccaro, D., Schasfoort, R.B., Mohri, Y., Nishimori, K., Mohammed, S., Heck, A.J., Clevers, H.

Nature 476(7360):293-7


Essential role for the d-Asb11 cul5 Box domain for proper notch signaling and neural cell fate decisions in vivo

Sartori da Silva, M.A., Tee, J.M., Paridaen, J., Brouwers, A., Runtuwene, V., Zivkovic, D., Diks, S.H., Guardavaccaro, D., Peppelenbosch, M.P.

PLoS One 5(11):e14023


TrCP- and Rsk1/2-mediated degradation of BimEL inhibits apoptosis

Dehan, E., Bassermann, F., Guardavaccaro, D., Vasiliver-Shamis, G., Cohen, M.S., Lowes, K.N., Dustin, M., Huang, D.S., Taunton, J., Pagano, M.

Mol Cell 33(1):109-16


KDM2A represses transcription of centromeric satellite repeats and maintains the heterochromatic state

Frescas, D., Guardavaccaro, D., Kuchay, S.M., Kato, H., Poleshko, A., Basrur, V., Elenitoba-Johnson, K.S., Katz, R.A., Pagano, M.

Cell Cycle 7(22):3539-47


The Cdc14B-Cdh1-Plk1 axis in the control of the G2 DNA damage response checkpoint

Bassermann, F., Frescas, D., Guardavaccaro, D., Busino, L., Peschiaroli, A., Pagano, M.

Cell 134(2):256-67


The HECT-domain ubiquitin ligase Ureb1 controls neural differentiation and proliferation by destabilizing the N-Myc oncoprotein

Zhao, X., Ik-Tsen Heng, J., Guardavaccaro, D., Jiang, R., Pagano, M., Guillemot, F., Iavarone, A., Lasorella, A.

Nat Cell Biol 10(6):643-53


Rac1 accumulates in the nucleus during the G2 phase of the cell cycle and promotes cell division

Michaelson, D., Abidi, W., Guardavaccaro, D., Zhou, M., Ahearn, I., Pagano, M., Philips, M.R.

J Cell Biol 181(3), 485-496


Control of chromosome stability by the βTRCP-REST-MAD2 axis

Guardavaccaro, D., Frescas, D., Dorrello, N.V., Peschiaroli, A., Multani, A.S., Cardozo, T., Lasorella, A., Iavarone, A., Chang, S., Hernando, E., Pagano, M.

Nature 452(7185) 365-70


The histone demethylase JHDM1B/FBXL10 is a nucleolar protein that represses transcription of ribosomal RNA genes

Frescas, D., Guardavaccaro, D., Bassermann, F., Koyama-Nasu, R., Pagano, M.

Nature 450(7167) 309-13


APC/CCdc20 controls the ubiquitin-mediated degradation of p21 in prometaphase

Amador, V., Ge, S., Santamaria, P.G., Guardavaccaro, D., Pagano, M.

Mol Cell 27(3):462-73


DRE-1, an evolutionarily conserved F-box protein that regulates C. elegans developmental age

Fielenbach, N., Guardavaccaro, D., Neubert, K., Chan, T., Li, D., Feng, Q., Hutter, H., Pagano M., Antebi A.

Dev Cell 12(3):443-55


SCFβTrCP- and S6K1-mediated degradation of PDCD4 promotes protein translation and cell growth

Dorrello, N.V., Peschiaroli, A., Guardavaccaro, D., Colburn, N.H., Sherman, N.E., Pagano, M.

Science 314(5798):467-71


SCFβTrCP-mediated degradation of Claspin regulates recovery from the DNA replication checkpoint response

Peschiaroli, A., Dorrello, N.V., Guardavaccaro, D., Venere, M., Halazonetis, T., Sherman, N.E., Pagano, M.

Mol Cell 23(3):319-29


Degradation of Id2 by the Anaphase Promoting Complex couples control of cell cycle exit and axonal growth

Lasorella, A., Stegmüller, J. Guardavaccaro, D., Liu, G., Carro, M.S., Rothschild, G., de la Torre-Ubieta, L., Pagano, M., Bonni, A., Iavarone, A.

Nature 442(7101):471-4


Skp2 contains a novel cyclin A binding domain that directly protects cyclin A from inhibition by p27

Ji, P., Goldin, L., Ren, H., Sun, D., Guardavaccaro, D., Pagano, M., Zhu, L.

J Biol Chem 281(33):24058-69


Mol Cell 22(1):1-4


Role of F-box protein βTrCP1 in mammary gland development and tumorigenesis

Kudo, Y.*, Guardavaccaro, D.*, Gonzalez Santamaria, P., Koyama-Nasu, R., Latres, E. Bronson, R. Yamasaki, L. Pagano M.

Mol Cell Biol 24(18):8184-8194


Oncogene 23(11):2037-49


Control of the SCFSkp2-Cks1 ubiquitin ligase by the APC/CCdh1 ubiquitin ligase

Bashir, T., Dorrello, N.V., Amador, V., Guardavaccaro, D., Pagano, M.

Nature 428(6979):190-3


Ubiquitin-mediated degradation of Cdc25A by βTrCP during S phase and in response to DNA damage

Busino, L., Donzelli, M., Chiesa, M., Guardavaccaro, D., Ganoth, D., Dorrello, N.V., Hershko, A., Pagano M., Draetta G.

Nature 426(6962):87-9


Control of meiotic and mitotic progression by the F-box protein βTrCP1 in vivo

Guardavaccaro, D., Kudo, Y. Boulaire, J., Barchi, M., Busino, L., Donzelli, M., Yamasaki, L., Pagano, M.

Dev Cell 4: 799–812


Neuroreport 13(4):417-22


Arrest of G(1)-S progression by the p53-inducible gene PC3 is Rb dependent and relies on the inhibition of cyclin D1 transcription

Guardavaccaro, D., Corrente, G., Covone, F., Micheli, L., D’Agnano, I., Starace, G., Caruso M., Tirone F.

Mol Cell Biol 20: 1797-815


Identification of a family of human F-box proteins

Cenciarelli, C., Chiaur, D. S., Guardavaccaro, D., Parks, W., Vidal, M., Pagano M.

Curr Biol 9: 1177-1179


Cell Growth Differ 7: 1327-1336


Inhibition of differentiation in myoblasts deprived of the interferon-related protein PC4

Guardavaccaro, D., Ciotti, M.T., Schafer, B.W., Montagnoli A., Tirone F.

Cell Growth Differ 6: 159-169


Nerve Growth Factor regulates the subcellular localization of the NGF inducible protein PC4 in PC12 cells

Guardavaccaro, D., Montagnoli, A., Ciotti, M.T., Lotti, L., Di Lazzaro, C., Torrisi, M.R., Gatti A., Tirone F.

J Neurosci Res 37: 660-674


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Group leader

Daniele Guardavaccaro

Daniele Guardavaccaro is group leader at the Hubrecht Institute. His group studies the Ubiquitin-Proteasome System (UPS), a system responsible for the regulated degradation of hundreds of cellular proteins in crucial signaling and disease systems. The Guardavaccaro group is interested in the molecular mechanisms by which the UPS regulates cell growth and proliferation. These processes are important during normal development and disease, such as cancer. Knowledge about the UPS in these processes can facilitate the improvement of molecular diagnostics and the development of new approaches to fight cancer.

Scientific training and positions

Group members

Daniele Guardavaccaro

Principal Investigator

Ilona den Hartog


Laurensia Yuniati


Zunamys Carrero


Manouk Gerritsen