HIPK2 is involved in cell proliferation and its suppression promotes growth arrest independently of DNA damage

The serine/threonine kinase homeodomain-interacting protein kinase 2 (HIPK2) is a co-regulator of an increasing number of transcription factors and cofactors involved in DNA damage response and development. We and others have cloned HIPK2 as an interactor of the p53 oncosuppressor, and have studied the role of this interaction in cell response to stress. Nevertheless, our original cloning of HIPK2 as a p53-binding protein, was aimed at discovering partners of p53 involved in cell differentiation and development, still controversial p53 functions. To this aim, we used p53 as bait in yeast two-hybrid screening of a cDNA library from mouse embryo (day 11 postcoitus) when p53 is highly expressed. In this study, we directly explored whether HIPK2 and p53 cooperate in cell differentiation. By measuring HIPK2 expression and activity in skeletal muscle and haemopoietic differentiation, we observed inverse behaviour of HIPK2 and p53 - excluding cooperation activity of these two factors in this event. However, by HIPK2 depletion experiments, we showed that drastic HIPK2 suppression promotes cell-cycle arrest by induction of the cyclin-dependent kinase inhibitor p21(Waf-1/Cip-1). HIPK2 activity is independent of DNA damage and takes place in cell-cycle-arresting conditions, such as terminal differentiation, growth factor deprivation, and G(0) resting. HIPK2 was found to be involved in cell-cycle regulation dependent on p21(Waf-1/Cip-1) and independent of DNA damage.