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Table of contents
Acknowledgements
Collaborations
Table of Contents
Abbreviations
Introduction
I) Discovery of ProMyelocytic Leukemia protein (PML)
1) Acute Promyelocytic Leukemia (APL)
2) The PML protein
3) PML Nuclear Bodies
II) Post-translational modifications
1) Diversity of post-translational modifications
2) Phosphorylation
3) Acetylation
4) SUMOylation
5) The SUMO/Ubiquitin coupled pathway
6) Ubiquitination
III) The SKP-Cullin-F-Box containing Complex (SCF)
1) General structure of Cullin-RING Ligases complex
2) The SCF complex and the F-Box proteins
3) Regulation of the SCF complex
4) Substrate recognition
5) SCFs and diseases
6) PML and SCF
IV) PML, a tumor suppressor
1) PML physiological functions
2) PML and diseases
3) PML and the apoptotic pathway
4) PML and the P53 pathway
5) PML and transcriptional regulation
6) Role of PML in DNA damage repair
7) PML and the Akt pathway
8) Cytoplasmic PML in tumorigenesis
9) PML in cancers
Thesis Objective
Results
I) Initial Data
1) Screen Design
2) Primary screen results
3) Validation screen
II) Functional study of selected candidates
1) Identification of SKP1a and RBX1
2) Manual validation of screen results
3) Depletion of SKP1a and RBX1 stabilizes PML
4) The overexpression of SKP1a and RBX1 destabilizes PML
5) RBX1 and SKP1a are both interacting with PML
6) Identification of the specific F-Box protein for PML
7) Validation of the interaction between PML and FBXO9
8) FBXO9 interacts with all PML isoforms
9) Localization of FBXO9-PML interaction
10) SUMOylation, arsenic and PML-FBXO9 interaction
11) FBXO9 degrades PML under arsenic trioxide treatment
12) Impact of FBXO9 on the half-life of PML
13) SCFFBXO9 ubiquitinates PML in vitro
14) An attempt to localize the FBXO9 degron on PML
15) Kinase mini-screen to localize the FBXO9 degron on PML
16) Search for physiological stimuli leading to SCFFBXO9-induced PML degradation
17) Possible links to diseases
Discussion and perspectives
1) SKP1a and RBX1 are members of an ubiquitination complex involved in the degradation of PML
2) The Cullin-1 is involved in SCF complexes
3) FBXO9 specifically interacts with PML
4) FBXO9 is involved in PML stability
5) Is PML degradation dependent on SUMOylation?
6) SCFFBXO9 specifically ubiquitinates PML
7) PML’s degron
8) Kinases phosphorylating PML’s degron
9) PML and FBXO9 in diseases
10) Mouse model Fbxo9 KO
11) PML and cellular differentiation
12) PML and innate immunity
13) The SCF complex: a druggable target
14) Other potential candidates to be studied
Conclusion
Material and Methods
Annexes
Annex 1: The 69 Mammalian F-Box proteins
Annex 2: F-Box protein and E3 ubiquitin ligase implication in cellular pathways
Annex 3: Validated candidates inducing a morphological change of PML Nuclear Bodies
Annex 4: Co-immunoprecipitation screen to identify PML interacting F-Box protein
Annex 5: Cell lines used in mRNA mini screen
Annex 6: FBXO9 is overexpressed in some types of breast cancers
Annex 7: Cancer tissue PML antibody staining of Breast and lung cancers
Bibliographical References
