Abstract
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 up-regulates 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 cells, but not in 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 up-regulation of p21 and BAX, dephosphorylation of Rb, and repression of cyclin A. Of importance, siRNA "knockdown" 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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / genetics
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Animals
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Apoptosis / genetics*
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Cell Line, Tumor
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cyclin A / biosynthesis
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Cyclin A / genetics
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics*
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G1 Phase / genetics*
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Hematopoietic Stem Cells / metabolism
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Interleukin-3 / immunology
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Interleukin-3 / pharmacology
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Mice
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Protein Binding / drug effects
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Protein Binding / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA, Small Interfering / genetics
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RNA, Small Interfering / pharmacology
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RNA-Binding Proteins / antagonists & inhibitors
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RNA-Binding Proteins / biosynthesis
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RNA-Binding Proteins / genetics*
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Transcription, Genetic / drug effects
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Transcription, Genetic / genetics
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Tumor Suppressor Protein p53 / biosynthesis
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Tumor Suppressor Protein p53 / genetics*
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Up-Regulation / drug effects
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Up-Regulation / genetics*
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bcl-2-Associated X Protein
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p21-Activated Kinases
Substances
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Bax protein, mouse
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Cyclin A
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DNA-Binding Proteins
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Interleukin-3
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RNA, Small Interfering
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RNA-Binding Proteins
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Tumor Suppressor Protein p53
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Zfp346 protein, mouse
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bcl-2-Associated X Protein
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Protein Serine-Threonine Kinases
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p21-Activated Kinases