The story of p53
Transcript of The story of p53
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
This presentation was prepared
by Varda Rotter Department of Molecular Cell Biology
The Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The history of p53 as seen by Varda Rotter
Presented at the12th p53 workshop in
New Zealand
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
Pre-history -1979
Name: The non-viral antigen 54KA keen of Large T antigen-makes a complex
Name: Cancer Associated p53Expresessed
in Methylcholantrn
transformed
fibroblastsName: p50
Expressed in retroviral transformed cells
Baptized as p53!!!
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
History: 1979-1989
The STRUCTURAL period!Bulding
of tools to study the gene and the protein!
Function: ONCOGENE!(no-kosher)
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
History: 1979-1989
The STRUCTURAL period!Bulding
of tools to study the gene and the protein!
Function: ONCOGENE!(no-kosher)
The story of p53
History: 1979-1989
The STRUCTURAL period!Bulding
of tools to study the gene and the protein!
Function: ONCOGENE!(no-kosher)
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19831983The first p53 workshop
The Marie Curie Memorial FoundationResearch InstituteThe ChartOxted, Surrey
The clonning
“saga”
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
p53 is a tumor marker:p53 protein expression in Small
Intestinal Carcinoma
6-12 October, 1983
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19871987The second p53 meeting
Centre d’Information ScientifqueDe L’A.R.C.VillejuifParis
The p53 genome era
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19881988The third p53 workshop
The Marie Curie Memorial FoundationResearch InstituteThe ChartOxted, Surrey
Still an ugly duckling!!We are still very confused!
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19901990The fourth p53 workshop
The Marie Curie Memorial FoundationResearch InstituteThe ChartOxted, Surrey
Turning into a beautiful Swan!!Am I tumor Suppressor gene???
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
History: 1990 critical year in the history of p53!!
*There is a wild type p53 proteinand there are many mutant p53 proteins!!
*Different half life of the proteins*Different activities
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
History: 1990-date
Wild type p53 is a tumor suppressor gene!!
Based on: in vitro studiesClinical evidencesK/O mice!
Did we study all those years the mutant p53 proteins??
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19911991The fifth p53 workshopPrinceton UniversityPRINCETONUSA
A beautiful Swan Indeed!A bona-fida tumor suppressor!!
*in vivo significance:in mouse and man!What about K/O mice?*Transcription factor*Apoptosis!!
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
II III IV VI
Transactivation Specific DNA binding
N C
2001001 393300
NLS1Proline rich Tetramerisation
Protein-protein interactions,Transcriptional repressionapoptosis
Negative regulation of DNA binding
The story of p53
History: 1992-dateThe “domain” periodsA transcription factor!!
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Spectrum of p53 mutation in human tumors IARC Database
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
6th p53 workshop Tibirias, Israel 1992
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19921992The Sixth p53 workshop
The Weizmann InstituteRehovot, Israel
The Sea of Galille, Israel
Functional Domains!Finally it makes sense!!
A new partner: mdm2The love loop!To be or not to be
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
The DNA binding period!
Binding Specific p53 consensus sequencesNon-specific DNA sequences
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19941994The seventh p53 workshopToronto, CanadaMuskoka
Just more good news:
*p53-DNA Crystals appeared!!*K/O mice-grow tumors!!*Germ line p53 mutations!!
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Structure of the p53 and its interaction with DNA
Clinical data make sense!!!
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19961996The eight p53 workshopDundeeScotland
P53-based therapy?
More about the p53-mdm2Relationship!!
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Ygal
Haupt, Jerusalem
Mdm2 inhibits p53 activities and promotes it for proteasomal degradation
How the p53-Mdm2 auto-regulatory loop is interrupted in response to stress?
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
19981998The ninth p53 workshopElunda
BeachCreteGreece
A wonderful meeting almost every one agrees with everyone!
Are we ready for the clinical trials?
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
Finally p53 finds a FAMILIA!
p73P63
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
p53 found a family
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
The story of p53
p53 gene therapy
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
p53 found a family
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
20002000The tenth p53 workshopMonterayUSA
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
20022002BarcelonaBarcelona
A great meeting organized byCarlos Cordon-Cardo
and
Carol PrivasNew YorkUSA
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
So where are we today???
p53 Mutation
p53
Loss of function
Oncogenic function
Dominant
negativeGain of function
Mutagenesis
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
When there is a will When there is a will there is a waythere is a way
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
20042004New New -- ZealandZealandA great meeting organized byAntony
Braithwaite
Dunedin, New Zealand
Varda Rotter, Weizmann Institute of Science, Rehovot, Israel
20062006USAUSA
Jill BrgonettiCarlos Cardon-CardoWei GuScott LoweArnold J. LevineJim ManfrediUte MollCarlo Privesa