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.)

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.).

PROTEINS ARE THE MACHINES OF OUR BODY

•Chemical processes (enzymes)

•Physical processes

•Regulators

•Immune response (antibodies)

There are many thousands of different proteinsin our cells, each of which has a specific function.

PROTEIN SYNTHESIS AND DEGRADATION

Amino acids Protein

DNA

RNA

Protein synthesis

Protein degradation…

MAIN FUNCTIONS OF PROTEIN DEGRADATION

amino acids

amino acids

1. Removal of abnormalor misfolded proteins prevents toxicity to cells

2. Degradation of normal regulatory proteins stops theiraction (“switch off”)

NORMAL PROTEIN

ABNORMAL PROTEIN

QUESTION:

HOW ARE CELLULAR PROTEINS DEGRADED AT

A HIGHLY SELECTIVE AND REGULATED MODE?

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

Ubiquitin- a protein that marks other proteins for degradation

Goldberg, 2005

PROTEINS ARE TAGGED FOR DEGRADATION BY LINKAGE TO UBIQUITIN CHAIN

Linkage of ubiquitin chainto protein by specific enzymes (E1, E2, E3)

Proteins linked to ubiquitin chains are

degraded by the proteasome

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 theubiquitin 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

THE CELL DIVISION CYCLE

G0/G1 TimeTime

Lev

elL

evel

S

p27Cyclin E Cyclin A

Skp2 Cks1

NON-DIVIDING CELLS

DIVIDING CELLS

Oscillation in levels of proteins that regulate cell division

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

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)

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

VELCADE - A HIGHLY EFFICIENT INHIBITOR OF THE PROTEASOME

Linkage of ubiquitin chainto protein by specific enzymes (E1, E2, E3)

Proteins linked to ubiquitin chains are

degraded by the proteasome

Velcade (Bortezomib, PS-341)

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 theirapoptosis

• Also effective in the treatment of mantle cell lymphoma

SOME THOUGHTS ON THE FUTURE OF HEALTHCARE IN THE 21ST CENTURY.

• Life expectancy ~ 90-100 years, accompaniedby prolonged quality of life

• Retirement age ~ 75 years

•New treatments for currently unsolved, majorhealth problems: cancer, neudegenerative and cardiovascular diseases

• Molecular medicine

• Individualized medicine

• Technology-based medicine

Technion lab (1971-present)

Dvora GanothHanna HellerEsther EytanSarah EliasJudith Hershko

Former graduate studentsAaron CiechanoverYuval ReissValery SudakinShirly Lahavand many others…

Collaboration and helpIrwin A. RoseJoan RudermanMichele Pagano

Present graduate studentsYakir MosheShirly MiniowitzAdar Teichman

Postdoctoral fellowsIlana BraunsteinDanielle Sitri-ShevahYelena Dumin