Submitted June 20, 2006
Accepted August 1, 2006
JAZ mediates G1 cell cycle arrest and apoptosis by positively regulating p53 transcriptional activity
Mingli Yang, Song Wu, Xuekun Su, and W S May*
University of Florida
* Corresponding author; email: smay{at}ufscc.ufl.edu.
We previously identified JAZ as a novel zinc finger (ZF) protein by screening a murine interleukin-3 (IL-3) dependent NFS/N1.H7 myeloid cell cDNA library. JAZ is a member of a new class of ZFPs that is evolutionarily conserved and preferentially binds to dsRNA but its function was unknown. Now we report that the stress of IL-3 growth factor withdrawal upregulates JAZ expression in hematopoietic cells in association with p53 activation and induction of cell death. Biochemical analysis reveals that JAZ associates with p53 to stimulate its transcriptional activity in p53 expressing but not p53-null cells unless complemented with p53. JAZ functions to mediate G1 cell cycle arrest followed by apoptosis in a p53-dependent mechanism that is associated with upregulation of p21 and BAX, dephosphorylation of Rb and repression of cyclin A. Importantly, siRNA-"knock-down" of endogenous JAZ inhibits p53 transcriptional activity, decreases the G1/G0 population and attenuates stress-induced cell death. While JAZ directly binds p53 in vitro in a mechanism requiring p53’ s C-terminal regulatory domain but independent of dsRNA, the dsRNA-binding ZF domains are required for JAZ’ s stimulatory role of p53 in vivo by dictating its nuclear localization. Thus, JAZ is a novel negative regulator of cell growth by positively regulating p53.
