The Functions and Regulation of Ornithine Decarboxylase

..............................................................................................................4 LIST OF ORIGINAL PUBLICATIONS...................................................................7 ABBREVIATIONS ...................................................................................................8 INTRODUCTION...................................................................................................10 REVIEW OF THE LITERATURE.........................................................................12 1. Functions of polyamines and ODC.................................................................................. 12 1.1. Polyamines bind nucleic acids ....................................................................................................12 1.2. Interaction of polyamines with proteins.....................................................................................14 1.3. Polyamines and the cell cycle/ cell proliferation .......................................................................18 1.4. In reproductive organs.................................................................................................................19 2. Regulation of ODC............................................................................................................. 20 2.1. Antizymes ....................................................................................................................................20 2.2. Antizyme inhibitors .....................................................................................................................22 2.3. Spatial regulation of ODC...........................................................................................................23 3. The actin cytoskeleton ....................................................................................................... 26 3.1. The regulation and functions of Rho ..........................................................................................26 3.2. The effect of polyamine regulation on the cytoskeleton ...........................................................31 4. Polyamines and ODC in diseases ..................................................................................... 32 4.1. Cancer...........................................................................................................................................32 4.2. Brain pathologies .........................................................................................................................34 AIMS OF THE STUDY ..........................................................................................38 MATERIAL AND METHODS ...............................................................................39 RESULTS AND DISCUSSION ..............................................................................40 1. ODC and the cytoskeleton ................................................................................................ 40 1.1. Transglutaminase mediates polyamination of RhoA ................................................................40 1.2. Polyamination of RhoA and the cell cycle.................................................................................41 1.3. Polyamination of RhoA and transformation ..............................................................................43 1.4. ODC-mediated spatial regulation of RhoA and reorganization of actin ..................................44 2. The structure and distribution of AZIN2....................................................................... 46 2.1. Comparison of the structures of ODC and AZIN2....................................................................46 2.2. Alternative splicing of AZIN2....................................................................................................48 2.3. Tissue distribution of AZIN2......................................................................................................52 2.4. Subcellular distribution of AZIN2..............................................................................................57 2.5. Functional implications of AZIN2 .............................................................................................59 CONCLUSIONS AND FUTURE PERSPECTIVES ..............................................64 ACKNOWLEDGMENTS........................................................................................66 REFERENCES.......................................................................................................68