Page 42 - Rappaport Institute Magazine 2024

CELL BIOLOGY AND CANCER SCIENCE
Aaron Ciechanover, MD, DSc Distinguished Technion Professor of Biochemistry
MD, 1974 – The Hebrew University of Jerusalem, Israel
DSc, 1982 – Technion, Israel
The ubiquitin system and diseases
All the current research projects in the laboratory are based on our discovery of regulated protein degradation mediated by the ubiquitin-mediated proteolytic system, a discovery that awarded us the 2004 Nobel Prize in Chemistry. As the process plays major roles in most basic cellular processes such as cell cycle and differentiation, communication of the cell with the extracellular environment and maintenance of the cellular quality control, it is not surprising that aberrations in the pathway have been implicated in the pathogenesis of many diseases, certain malignancies and neurodegenerative disorders among them. Consequently, the system has become a major platform for drug targeting. Current studies in our laboratory focus on the involvement of the ubiquitin system in the pathogenesis of malignancies and tumor suppression (via activation or inactivation of the transcription factor NF-KB; 1-3), and neurodegeneration (4) and on metabolic regulation of the system as a novel platform to develop anti-cancer drugs (5).
Selected Publications
ˆ 1 – Kravtsova-Ivantsiv, Y., Shomer, I., Cohen-Kaplan, V., Snijder, B.,
Superti-Furga, G., Gonen, H., Sommer, T., Ziv, T., Admon, A., Naroditky, I., Jbara, M., Brik, A., Pikarsky, E., Kwon, Y.T. Doweck, I., and Ciechanover, A. (2015). KPC1-mediated ubiquitination and Proteasomal Processing of NF-κB p105 to p50 Restricts Tumor Growth. Cell 161, 333-347.
ˆ 2 – Kravtsova-Ivantsiv ,Y., Goldhirsh, G., Ivantsiv, A., Ben Itzhak, O., Kwon, Y.T., Pikarsky, E., and Ciechanover, A. (2020). Excess of the NF-KB p50 subunit generated
by the ubiquitin ligase KPC1 suppresses tumors via PD-L1- and chemokines-mediated mechanisms. Proc. Natl. Acad. Sci. USA. doi: 10.1073/pnas.2019604117.
ˆ 3 – Goldhirsh, G., Kravtsova-Ivantsiv, Y., Satish, G., Ziv, T., Brik, A. and Ciechanover, A. (2021). A short binding site in the KPC1 ubiquitin ligase mediates processing of
NF-KB1 p105 to p50: A potential for a tumor-suppressive PROTAC. Proc. Natl. Acad. Sci. USA, 118:e2117254118.
doi: 10.1073/pnas.2117254118. PMID: 34873064
ˆ 4 – Hakim-Eshed, V., Boulos, A., Cohen-Rosenzweig, C., Libo Yu-Taegerd, L., Ziv, T., Kwon, Y.-T., Riess, O., Nguyen, H.H.P., Ziv, N.E., and Ciechanover, A. (2020). Site-specific ubiquitination of pathogenic huntingtin attenuates its deleterious effects. Proc. Natl. Acad. Sci, USA. 117, 18661-18669 www.pnas.org/cgi/doi/10.1073/pnas.2007667117
ˆ 5 – Livneh, I., Cohen-Kaplan, V., Fabre, B., Abramovitch, I., Lulu, C., Nataraj, N.B., Lazar., I., Ziv, T., Yarden., Y., Yaniv, Z., Gottlieb, E., and Ciechanover, A. (2023). Regulation of Nucleo-Cytosolic 26 Proteasome Translocation by Aromatic
Amino Acids via mTOR Signaling is Essential for Cell Survival Under Stress. Mol. Cell 83, 3333-3346.e5. doi: 10.1016/j.molcel.2023.08.016. PMID: 37738964
Grants and Awards
2000 – The Albert and Mary Lasker Award for Basic Medical Research (shared with Drs. Avram Hershko and Alexander Varshavsky)
2002 – EMET (Truth) Prize (Israeli Prime Minister Prize), for Arts, Sciences and Culture (in Life Sciences and Medicine; shared with Drs. Avram Hershko and Leo Sachs)
2003 – The Israel Prize for Biology
2004 – Nobel Prize in Chemistry (shared with Drs. Avram Hershko and Irwin A. Rose) Memberships in scholarly bodies (selected):
2007 – Associate (Foreign). National Academy of Sciences of the USA
(NAS USA)
2008 – Associate (Foreign). National Academy of Medicine ((NAM)
2013 – Fellow, American Academy for Cancer Research (AACR)
aaroncie@technion.ac.il
Aaron ciechanover Lab
The five elongated cap cells of the lateral chordotonal organ are anchored to the larval body wall via two