Identification of BERP (brain-expressed RING finger protein) as a p53 target gene that modulates seizure susceptibility through interacting with GABA(A) receptors.
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(A)R)-mediated miniature inhibitory postsynaptic currents as well as reduced surface protein expression of GABA(A)Rs containing the gamma2-subunit. However, BERP deficiency did not decrease GABA(A)Rgamma2 mRNA levels, raising the possibility that BERP may act at a posttranscriptional level to regulate the intracellular trafficking of GABA(A)Rs. Our results indicate that BERP is a unique p53-regulated gene and suggest a role for p53 within the central nervous system.
Cheung
Carol C
CC
The Campbell Family Cancer Research Institute, University Health Network, Toronto, ON, Canada M5G 2M9.
Yang
Caimei
C
Berger
Thorsten
T
Zaugg
Kathrin
K
Reilly
Patrick
P
Elia
Andrew J
AJ
Wakeham
Andrew
A
You-Ten
Annick
A
Chang
Ning
N
Li
Lijun
L
Wan
Qi
Q
Mak
Tak Wah
TW
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D003292:Convulsants / Q000633:toxicity; D017931:DNA Primers / Q000235:genetics; D016158:Genes, p53; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D010433:Pentylenetetrazole / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015854:Up-Regulation
C120405:BERP; D002352:Carrier Proteins; D003292:Convulsants; D017931:DNA Primers; C546279:GABRG2 protein, human; C546280:Gabrg2 protein, mouse; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D011963:Receptors, GABA-A; C426543:TRIM3 protein, human; D016159:Tumor Suppressor Protein p53; D010433:Pentylenetetrazole