Cooperative Role of the RNA-Binding Proteins Hzf and HuR in p53 Activation

The RNA-binding protein Hzf (hematopoietic zinc finger) plays important roles in mRNA translation in cerebellar Purkinje cells and adipocytes. We along with others have reported that the expression of the Hzf gene is transcriptionally regulated by the p53 tumor suppressor protein. We show here that Hzf regulates p53 expression in cooperation with HuR. Hzf and HuR independently interact with the 3' untranslated region (UTR) of p53 mRNA, which facilitates the cytoplasmic localization of p53 mRNA in the presence of the ARF tumor suppressor protein. In the absence of Hzf and HuR, p53 induction by p19(ARF) is significantly attenuated, and the cells consequently acquire resistance to p19(ARF). Thus, these findings demonstrate that in addition to Mdm2 inhibition, p19(ARF) increases the concentration of p53 through posttranscriptional control of p53 mRNA and suggest critical roles for the RNA-binding proteins Hzf and HuR in p53 induction.