Abstract
PA28γ (also called REGγ, 11Sγ or PSME3) negatively regulates p53 activity by promoting its nuclear export and/or degradation. Here, using the RNA ligase-mediated rapid amplification of cDNA ends (RLM-RACE) method, we identified the transcription start site of the PA28γ gene. Assessment with the luciferase assay demonstrated that the sequence −193 to +16 is the basal promoter. Three p53 binding sites were found within the PA28γ promoter utilizing a bioinformatics approach and were confirmed by chromatin immunoprecipitation and biotinylated DNA affinity precipitation experiments. The p53 protein promotes PA28γ transcription, and p53-stimulated transcription of PA28γ can be inhibited by PA28γ itself. Our results suggest that PA28γ and p53 form a negative feedback loop, which maintains the balance of p53 and PA28γ in cells.
Highlights
The proteasome is a multi-subunit proteolytic complex containing a cylindrical 20S catalytic core particle (20S proteasome) and two regulatory particles
PA28γ has been reported to target the degradation of the cell cycle inhibitors p21Cip1, p16INK4a and p19Arf in an ubiquitin-independent manner [5,6,7]
These results suggest that PA28γ functions as an oncogene
Summary
The proteasome is a multi-subunit proteolytic complex containing a cylindrical 20S catalytic core particle (20S proteasome) and two regulatory particles (proteasomal activator). PA28 ( called 11S activator, REG) and PA200 activate the ubiquitin- and ATP-independent proteolytic function of the 20S proteasome (reviewed by Tanaka [1]). PA28γ has been reported to target the degradation of the cell cycle inhibitors p21Cip, p16INK4a and p19Arf in an ubiquitin-independent manner [5,6,7]. It inhibits the activity of the tumor suppressor p53 by promoting its nuclear export and mouse double minute 2 homolog (MDM2)-mediated degradation [8,9]. Cells with a depleted expression of PA28γ or over-expression of a dominant-negative PA28γ mutant demonstrate a marked aneuploidy, supernumerary centrosomes, and multipolarity [18]
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