Identification of BERP (brain-expressed RING finger protein) as a p53 target gene that modulates seizure susceptibility through interacting with GABA_A receptors

摘要

P53 is a central player in responses to cellular stresses and a major tumor suppressor. The identification of unique molecules within the p53 signaling network can reveal functions of this important transcription factor. Here, we show that brain-expressed RING finger protein (BERP) is a gene whose expression is up-regulated in a p53-dependent manner in human cells and in mice. We generated BERP-deficient mice by gene targeting and demonstrated that they exhibit increased resistance to pentylenetetrazol-induced seizures. Electrophysiological and biochemical studies of cultured cortical neurons of BERP-deficient mice showed a decrease in the amplitude of GABA_A receptor (GABA_AR)-mediated miniature inhibitory postsynaptic currents as well as reduced surface protein expression of GABA_A Rs containing the γ_2-subunit. However, BERP deficiency did not decrease GABA_ARγ_2 mRNA levels, raising the possibility that BERP may act at a posttranscriptional level to regulate the intracellular trafficking of GABA_ARs. Our results indicate that BERP is a unique p53-regulated gene and suggest a role for p53 within the central nervous system.