1. GREAT CHANGES IN HEALTH CARE IN THE PAST 40 YEARS Large increase in life expectancy Great improvements in prevention of disease ( cardiovascular: statins, hypertension management, lifestyle, etc.) Improvements in diagnosis and early detection (imaging: CT, MRI, US; other technology-related; molecular diagnosis) Improvements in treatment of disease (technology-related: intensive care, pacemakers, etc.; novel drugs: cancer chemotherapy, AIDS, etc.)

2. ROLES OF SCIENTIFIC DISCOVERY IN THE IMPROVEMENT OF HEALTH CARE. 1.Basic research and discovery provides the foundation for great advances in medical practice (Fleming & penicillin; Lauterbur & MRI, etc.). 2. Applied research and development are always based on discoveries in basic research. It benefits directly healthcare (i. e., coronary stents, laparoscopic & robotic surgery, new generations of antibiotics, etc.).

3. PROTEINS ARE THE MACHINES OF OUR BODY Chemical processes (enzymes) Physical processes Regulators Immune response (antibodies) There are many thousands of different proteins in our cells, each of which has a specific function.

4. PROTEIN SYNTHESIS AND DEGRADATION Amino acids Protein DNA RNA Protein synthesis Protein degradation …

5. MAIN FUNCTIONS OF PROTEIN DEGRADATION amino acids amino acids 1.Removal of abnormal or misfolded proteins prevents toxicity to cells 2. Degradation of normal regulatory proteins stops their action (“switch off”) NORMAL PROTEIN ABNORMAL PROTEIN

6. QUESTION: HOW ARE CELLULAR PROTEINS DEGRADED AT A HIGHLY SELECTIVE AND REGULATED MODE?

7. STAGES AND MILESTONES IN THE RESEARCH 1969-71: The degradation of tyrosine aminotransferase in cells requires energy 1977-78: Isolation of a small protein (ubiquitin) required for energy- dependent protein degradation 1979-1980: Discovery of linkage of ubiquitin to proteins destined for degradation; proposal of the ubiquitin tagging hypothesis 1980- 1990: Identification of enzymes involved in ubiquitin-mediated protein degradation 1990-present: Roles of the ubiquitin system in the control of cell division

8. Ubiquitin- a protein that marks other proteins for degradation

9. Goldberg, 2005 PROTEINS ARE TAGGED FOR DEGRADATION BY LINKAGE TO UBIQUITIN CHAIN Linkage of ubiquitin chain to protein by specific enzymes (E1, E2, E3) Proteins linked to ubiquitin chains are degraded by the proteasome

10. STAGES AND MILESTONES IN THE RESEARCH 1969-71: The degradation of tyrosine aminotransferase requires energy 1977-78: Isolation of a small protein (ubiquitin) required for energy- dependent protein degradation 1979-1980: Discovery of ligation of ubiquitin to proteins; proposal of the ubiquitin tagging hypothesis 1980- 1990: Identification of enzymes involved in ubiquitin-mediated protein degradation 1990-present: Roles of the ubiquitin system in the control of cell division

11. THE CELL DIVISION CYCLE

12. G0/G1 Time Level S p27 Cyclin E Cyclin A Skp2 Cks1 NON-DIVIDING CELLS DIVIDING CELLS  Oscillation in levels of proteins that regulate cell division

13. Some roles of ubiquitin-mediated protein degradation. Control of cell division Signal transduction Regulation of gene expression Responses to inflammation Immune response Embryonic development Apoptosis Protein quality control by removal of abnormal proteins

14. INVOLVEMENT OF THE UBIQUITIN SYSTEM IN DISEASES Cancer (many types) Neurodegenerative diseases: Parkinson’s; Alzheimer’s; Huntington’s Mental retardation (Angelman’s syndrome) Viral diseases (AIDS virus multiplication) Muscle wasting (cachexia)

15. INVOLVEMENT OF THE UBIQUITIN SYSTEM IN CANCER (1) ONCOPROTEIN TUMOR SUPPRESSOR PROTEIN CELL DIVISION CANCER CAN BE CAUSED BY LACK OF DEGRADATION OF AN ONCOPROTEIN, OR BY TOO RAPID DEGRADATION OF A TUMOR SUPPRESSOR PROTEIN. Decreased degradation Increased degradation

16. VELCADE - A HIGHLY EFFICIENT INHIBITOR OF THE PROTEASOME Linkage of ubiquitin chain to protein by specific enzymes (E1, E2, E3) Proteins linked to ubiquitin chains are degraded by the proteasome Velcade (Bortezomib, PS-341)

17. VELCADE (BORTEZOMIB) PROTEASOME INHIBITOR Approved by FDA at 2003 for the treatment multiple myeloma, a bone marrow cancer Inhibits the proliferation of myeloma cells and promotes their apoptosis Also effective in the treatment of mantle cell lymphoma

18. SOME THOUGHTS ON THE FUTURE OF HEALTHCARE IN THE 21 ST CENTURY. Life expectancy ~ 90-100 years, accompanied by prolonged quality of life Retirement age ~ 75 years New treatments for currently unsolved, major health problems: cancer, neudegenerative and cardiovascular diseases Molecular medicine Individualized medicine Technology-based medicine

19. Technion lab (1971-present) Dvora Ganoth Hanna Heller Esther Eytan Sarah Elias Judith Hershko Former graduate students Aaron Ciechanover Yuval Reiss Valery Sudakin Shirly Lahav and many others… Collaboration and help Irwin A. Rose Joan Ruderman Michele Pagano Present graduate students Yakir Moshe Shirly Miniowitz Adar Teichman Postdoctoral fellows Ilana Braunstein Danielle Sitri-Shevah Yelena Dumin