Phospho-regulation at the crossroads of cell proliferation and DNA-damage control
NIPP1 is an inhibitor of protein phosphatase-1 (PP1) and controls key
signaling pathways of cell proliferation, DNA-damage signalling and
oncogenesis. With this research project we propose to explore the
molecular basis of NIPP1 functions. Using newly developed mousemodels
and cell-based tools we will examine whether the established NIPP1
functions are all mediated by associated PP1. We will also investigate
whether NIPP1 is a DNA-damage checkpoint component that can be
inactivated to induce a cell-cycle arrest and promote DNA repair via a newly
identified signaling complex that is scaffolded by protein kinase ATM.
Finally, we will examine whether the insensitivity of NIPP1-depleted
tissues and cultured cells to mutagens is explained by an enhanced
ATM-controlled DNA-repair capacity, senescence of tumor-forming stem
cells, and/or an adaptive immune response. This basic research project will
generate mechanistic insights that can possibly be exploited for the design
of novel therapies that target key oncogenic signaling pathways.