Guardavaccaro: Ubiquitine-ligases en kanker

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De Guardavaccaro groep bestudeert de functies van het ubiquitine-systeem in normale cellen en hoe deregulatie van dit systeem leidt tot de vorming van kanker.

Het onderzoek in ons laboratorium richt zich op het bestuderen van de moleculaire mechanismen waarmee het ubiquitine-systeem de celgroei en -proliferatie controleert, en het begrijpen hoe deregulatie van dit netwerk bijdraagt aan maligne transformatie. Onze groep is met name geïnteresseerd in de rol van Cullin-RING-complexen, de grootste klasse van E3-ubiquitine-ligases in eukaryoten.

Cullin-RING-ubiquitine-ligasen (CRL’s) delen een gemeenschappelijke katalytische kern, die bestaat uit een Cullin-skelet en een RING-eiwit, dat fungeert als de koppelingsplaats voor ubiquitine-conjugatie-enzymen. De katalytische kern van CRL assembleert met talrijke substraatreceptoren, die zich richten op specifieke substraten voor de ubiquitinering. Vanwege de grote diversiteit van hun substraatreceptorsubeenheden zijn meer dan 200 afzonderlijke CRL’s aanwezig in eukaryote cellen, waardoor deze enzymen worden aangemerkt als belangrijke bemiddelaars van ubiquitine-conjugatie en sleutelregelaars van een breed scala van biologische processen.

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

Download|

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.

Download|2013

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.

Download|2008

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.

Download|2003

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.

Download|2012

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.

Download|2006

Overige publicaties

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

Download|2015

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

Download|2014

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

Download|2014

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

Download|2014

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

Download|2014

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

Download|2013

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)

Download|2013

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

Download|2013

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

Download|2012

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

Download|2012

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

Download|2012

Science Signaling 5(219):pe155

Download|2012

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

Download|2011

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

Download|2010

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

Download|2009

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

Download|2008

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

Download|2008

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

Download|2008

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

Download|2008

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

Download|2008

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

Download|2007

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

Download|2007

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

Download|2007

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

Download|2006

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

Download|2006

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

Download|2006

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

Download|2006

Mol Cell 22(1):1-4

Download|2006

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

Download|2004

Oncogene 23(11):2037-49

Download|2004

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

Download|2004

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

Download|2003

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

Download|2003

Neuroreport 13(4):417-22

Download|2002

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

Download|2000

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

Download|1999

Cell Growth Differ 7: 1327-1336

Download|1996

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

Download|1995

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

1994

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Groepsleider

Daniele Guardavaccaro

Daniele Guardavaccaro is groepsleider bij het Hubrecht Institute. Zijn groep onderzoekt het Ubiquitin-Proteasome System (UPS), een systeem dat verantwoordelijk is voor de gereguleerde afbraak van honderden cellulaire eiwitten in cruciale signalerings- en ziektesystemen. De Guardavaccaro groep is geïnteresseerd in de moleculaire mechanismen waarmee het UPS celgroei en -proliferatie reguleert. Deze processen zijn belangrijk voor de normale ontwikkeling, maar ook bij ziekten zoals kanker. Kennis van het UPS kan de moleculaire diagnostiek en de ontwikkeling van nieuwe invalshoeken voor de behandeling van kanker verder helpen.

Wetenschappelijke opleiding en posities


Groepsleden

Daniele Guardavaccaro

Group Leader

Ilona den Hartog

Technician

Laurensia Yuniati

Postdoc

Zunamys Carrero

Postdoc

Manouk Gerritsen

Student