Biochemical and Functional Analysis of the PREP1 Interactor: p160 Myb Binding Protein 1

Mori, Silvia (2010). Biochemical and Functional Analysis of the PREP1 Interactor: p160 Myb Binding Protein 1. PhD thesis The Open University.



p160 myb binding protein 1a (p160) is a nucleolar protein the function of which is poorly understood. To date, only a few interactors, mainly transcription factors (e.g. Myb, Jun), have been characterized. One of these is Prep1, an homeodomain transcription factor essential for embryonic development, involved, in particular, in haemopoiesis, angiogenesis, and oculogenesis, as well as in apoptosis and tumorigenesis. In this thesis work I show that p160 is capable of binding Prep1 through the same region as another Prep1 interactor, Pbx, and that such binding inhibits Prepl action on the HoxB enhancer. I demonstrate that the two proteins, Prep1 and p160, interact mainly in the nucleoplasm and hence only under conditions that favor p160 translocation from the nucleolus to the nucleoplasm (e.g. after treatment with Actinomycin D).

Moreover I studied p160 during cell-cycle, since during mitosis p160 assumes a para-chromosomal localization. In HeLa cells, depletion of p160 by siRNA transfection decreases the proliferation rate and increases cell-death, mostly via apoptosis. p160-depleted HeLa cells accumulate in the G2/M phases of the cell-cycle and show a variety of mitotic defects: extended division time and structural alterations of the metaphasic plate. All these data suggest that p160 is essential for proper cell division. This phenotype is also in agreement with my observations that p160 down-regulated NIH 3T3 cells are more sensitive to transformation by Ras and Myc and undergo spontaneous neoplastic transformation even in the absence of oncogenes.

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